Phosphonoformic acid esters and pharmaceutical compositions containing same

ABSTRACT

A pharmaceutical preparation containing as active ingredient a compound of the formula ##STR1## wherein R 1  and R 2  are the same or different, and each is selected from the group consisting of hydrogen, alkyl groups containing 1-6 carbon atoms; cycloalkyl groups containing 3-6 carbon atoms; cycloalkyl-alkyl groups containing 4-6 carbon atoms; 1-adamantyl; 2-adamantyl, benzyl; and phenyl groups of the formula ##STR2## wherein R 4  and R 5  are the same or different and each is selected from the group consisting of hydrogen, halogen, alkyl having 1, 2, or 3 carbon atoms, alkoxy having 1, 2, or 3 carbon atoms, alkoxycarbonyl having 2-7 carbon atoms and alkylcarbonyl groups having 2-7 carbon atoms; or R 4  and R 5  together form a straight saturated alkylene chain having 3 or 4 carbon atoms and being bound to adjacent positions, i.e. 2,3- or 3,4- in the phenyl ring; and R 3  is selected from the group consisting of hydrogen, alkyl groups containing 1-8 carbon atoms; cycloalkyl groups containing 3-8 carbon atoms; cycloalkyl-alkyl groups containing 4-8 carbon atoms; 1-adamantyl; 2-adamantyl; benzyl; and phenyl groups of the formula ##STR3## wherein R 4  and R 5  have the meaning given above; provided that at least one of the groups R 1 , R 2  and R 3  is alkyl, cycloalkyl, or cycloalkyl-alkyl as defined above, or 1-adamantyl, 2-adamantyl, or benzyl; and provided that when R 3  is H, then one of R 1  and R 2  is alkyl, cycloalkyl, or cycloalkyl-alkyl as defined above, or 1-adamantyl, 2-adamantyl, or benzyl and the other of R 1  and R 2  is H; or a physiologically acceptable salt or an optical isomer thereof; novel compounds within formula I, methods for their preparation and their medicinal use.

This application is a divisional of Application Ser. No. 093,167, filedon Nov. 13, 1979, now U.S. Pat. No. 4,386,081, which is acontinuation-in-part of application Ser. No. 971,896, filed on Dec. 21,1978, now abandoned.

FIELD OF THE INVENTION

The present invention relates to novel pharmaceutical compositions andto a novel method for selectively combating viruses, such as herpesviruses, influenza viruses, etc., which can cause various diseases inanimals including man. Such diseases include common infections. In thosecases where, the active ingredient in the composition is a novelcompound, the invention also comprises the novel compounds per se andprocesses for their preparation.

BACKGROUND OF THE INVENTION

The effects of viruses on bodily functions is the end result of changesoccuring at the cellular and subcellular levels. The pathogenic changesat the cellular level are different for different combinations ofviruses and host cells.

Important common viral infections are herpes dermatitis (includingherpes labialis), herpes keratitis, herpes genitalis, herpes zoster,herpes encephalitis, infectious mononucleosis and cytomegalovirusinfections all of which are caused by viruses belonging to theherpesvirus group. Other important viral diseases are influenza A and Bwhich are caused by influenza A and B virus respectively. Anotherimportant common viral disease is viral hepatitis and especiallyhepatitis B virus infections are widely spread. Effective and selectiveantiviral agents are needed for the treatment of these diseases.

A most important common feature of the interaction between viruses andcells is the replication or transcription of the specific viral geneticinformation carried by viral nucleic acids. These viral nucleic acidsare of two kinds, deoxyribonucleic acids (DNA) or ribonucleic acids(RNA). The primary genetic information of the cell is carried by cellDNA. DNA and RNA synthesis involves complex enzymes called DNA and RNApolymerases respectively. The genetic information is transferred to thenew nucleic acid from a template nucleic acid. There are four generalways in which these nucleic acids can be replicated or transcribed.##STR4## Processes 1 and 3 are used by cells. DNA viruses such asherpesviruses also use process 1 but the enzyme is different from thatof the cell. RNA viruses such as influenza virus use process 2. There isa need for an effective antiviral agent preferably having a selectiveinhibiting effect on a specific viral function of the virus to becombated. It is, therefore, a general object of the present invention toprovide a novel method for combating virus infections using an antiviralagent which exerts a selective inhibiting effect on viral functions butwhich exerts only a negligible inhibiting effect on functions of thehost cells.

THE INVENTION

It has been found according to the present invention that the compoundsof the formula ##STR5## wherein R₁ and R₂ are the same or different, andeach is selected from the group consisting of hydrogen, alkyl groupscontaining 1-6 carbon atoms; cycloalkyl groups containing 3-6 carbonatoms: cycloalkyl-alkyl groups containing 4-8 carbon atoms; 1-adamantyl;2-adamantyl, benzyl; and phenyl groups of the formula ##STR6## whereinR₄ and R₅ are the same or different and each is selected from the groupconsisting of hydrogen, halogen, alkyl having 1, 2, or 3 carbon atoms,alkoxy having 1, 2 or 3 carbon atoms, alkoxycarbonyl having 2-7 carbonatoms and alkylcarbonyl groups having 2-7 carbon atoms; or R₄ and R₅together form a straight saturated alkylene chain having 3 or 4 carbonatoms and being bound to adjacent positions, i.e. 2,3- or 3,4- in thephenyl ring; and R₃ is selected from the group consisting of hydrogen,alkyl groups containing 1-8 carbon atoms; cycloalkyl groups containing3-8 carbon atoms; cycloalkyl-alkyl groups containing 4-8 carbon atoms;1-adamantyl; 2-adamantanyl; benzyl; and phenyl groups of the formula##STR7## wherein R₄ and R₅ have the meaning given above; provided thatat least one of the groups R₁, R₂ and R₃ is alkyl, cycloalkyl, orcycloalkyl-alkyl as defined above, or 1-adamantyl, 2-adamantyl, orbenzyl; and provided that when R₃ is H, then one of R₁ and R₂ is alkyl,cycloalkyl, or cycloalkyl-alkyl as defined above, or 1-adamantyl,2-adamantyl, or benzyl and the other of R₁ and R₂ is H; andphysiologically acceptable salts thereof, inhibit certain viralfunctions including the multiplication of viruses.

It is understood that the reference to "physiologically acceptablesalts" of the compounds of the formula I in the present specificationand claims relates only to such compounds which can form salts.Compounds wherein at least one of R₁, R₂ and R₃ is hydrogen can formsalts. Compounds wherein all of R₁, R₂ and R₃ are different fromhydrogen do not form salts.

Since the compounds of the formula I, when R₁ and R₂ are different,contain an asymmetric center, they exist in the form of optically activeforms, and can be resolved into their optical antipodes by knownmethods.

In this specification, the compounds of the invention are named asderivatives of the compound hydroxycarbonylphosphonic acid, whichcompound also is known under the name phosphonoformic acid.

The two provisions in the definition of the compounds of the inventionmean that the radicals R₁, R₂ and R₃ in formula I can be combined asillustrated in the following tabulation. It is understood that R₁ andR₂, which are the same or different, are considered as equivalent andinterchangeable in the table below.

    ______________________________________                                        R.sub.1      R.sub.2       R.sub.3                                            ______________________________________                                        alkyl, cycloalkyl,                                                                         H             H                                                  cycloalkyl-alkyl,                                                             1-adamantyl, 2-ada-                                                           mantyl, benzyl                                                                alkyl, cycloalkyl,                                                                         H             alkyl, cycloalkyl,                                 cycloalkyl-alkyl,          cycloalkyl-alkyl,                                  1-adamantyl, 2-ada-        1-adamantyl, 2-ada-                                mantyl, benzyl,            mantyl, benzyl,                                    phenyl groups of           phenyl groups of                                   formula II                 formula II                                         alkyl, cycloalkyl,                                                                         H             phenyl groups of                                   cycloalkyl-alkyl,          formula II                                         1-adamantyl, 2-ada-                                                           mantyl, benzyl                                                                phenyl groups of                                                                           H             alkyl, cycloalkyl,                                 formula II                 cycloalkyl-alkyl,                                                             1-adamantyl, 2-ada-                                                           mantyl, benzyl                                     alkyl, cycloalkyl,                                                                         alkyl, cycloalkyl,                                                                          phenyl groups                                      cycloalkyl-alkyl,                                                                          cycloalkyl-alkyl,                                                                           of formula II                                      1-adamantyl, 2-ada-                                                                        1-adamantyl, 2-ada-                                              mantyl, benzyl,                                                                            mantyl, benzyl,                                                  phenyl groups                                                                              phenyl groups of                                                 of formula II                                                                              formula II                                                       alkyl, cycloalkyl,                                                                         phenyl groups of                                                                            alkyl, cycloalkyl,                                 cycloalkyl-alkyl,                                                                          formula II    cycloalkyl-alkyl,                                  1-adamantyl, 2-ada-        1-adamantyl, 2-ada-                                mantyl, benzyl,            mantyl, benzyl,                                    phenyl groups of           phenyl groups of                                   formula II                 formula II                                         alkyl, cycloalkyl,                                                                         phenyl groups of                                                                            phenyl groups of                                   cycloalkyl-alkyl                                                                           formula II    formula II                                         1-adamantyl, 2-ada-                                                           mantyl, benzyl                                                                alkyl, cycloalkyl,                                                                         alkyl, cycloalkyl,                                                                          alkyl, cycloalkyl,                                 cycloalkyl-alkyl,                                                                          cycloalkyl-alkyl,                                                                           cycloalkyl-alkyl,                                  1-adamantyl, 2-ada-                                                                        1-adamantyl, 2-ada-                                                                         1-adamantyl, 2-ada-                                mantyl, benzyl,                                                                            mantyl, benzyl,                                                                             mantyl, benzyl,                                    phenyl groups of                                                                           phenyl groups of                                                                            phenyl groups of                                   formula II   formula II    formula II                                         H            H             alkyl, cycloalkyl,                                                            cycloalkyl-alkyl,                                                             1-adamantyl, 2-ada-                                                           mantyl, benzyl                                     ______________________________________                                    

The first provision means that in the above table, combinations whereinR₁, R₂ and R₃ all are H or phenyl groups of formula II are excluded.

The compounds of the formula I and physiologically acceptable saltsthereof are useful in therapeutic and/or prophylactic treatment of viraldiseases.

PRIOR ART

The compounds of the formula I are esters of phosphonoformic acid.Various esters of phosphonoformic acid are described in for example U.S.Pat. Nos. 3,943,201, 3,155,597, 3,533,995, and in Chem. Ber. 57 p1023(1924), Chem. Ber. 60B, p291 (1927), and in Chem. Pharm. Bull. 21 (5),p1160 (1973). However, these esters have not been suggested for anypharmacological use.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides

A. A method for treatment of diseases caused by viruses in animalsincluding man, comprising administering to an animal so infected totherapeutically effective amount of a compound of the formula I or aphysiologically acceptable salt thereof.

B. A method for the treatment of diseases caused by viruses in animalsincluding man, by inhibiting the activity of viral polymerase,characterized by administering to an animal so infected a compound ofthe formula I or a physiologically acceptable salt thereof in an amounteffective for inhibiting the activity of said viral polymerase.

C. A method for inhibiting the multiplication of virus, in particularherpesviruses, influenza virus and hepatitis B virus, and retrovirusesin animals including man, by administering to an animal in need of suchtreatment a compound of the formula I or a physiologically acceptablesalt thereof in an amount sufficient for inhibiting said multiplication.

D. A method for inhibiting the growth of virus-transformed cells inanimals including man, characterized by administering to an animal inneed of such treatment a compound of the formula I or a physiologicallyacceptable salt thereof in an amount sufficient for inhibiting saidgrowth.

The invention also relates to the use of a compound of the formula I ora physiologically acceptable salt thereof, in each of the above givenmethods, A, B, C, D, E, F, G, H, and I. For example, the inventionrelates to the use of a compound of the formula I or a physiologicallyacceptable salt thereof, for

(a) inhibiting the replication of virus in animals including man, inparticular herpesvirus, influenza virus and hepatitis B viruses; and

(b) for inhibiting the growth of virus-transformed cells in animalsincluding man.

Furthermore, the invention provides pharmaceutical preparationscomprising as active ingredient a compound of the formula I or aphysiologically acceptable salt thereof, optionally in association witha pharmaceutically acceptable carrier. The invention also encompasses aprocess for the preparation of a medicine having antiviral acitivity,characterized in that a compound of the formula I or a physiologicallyacceptable salt thereof is brought into an administration form suitablefor therapeutical purposes, and the shaped medicine obtained by suchprocess.

Most of the compounds within the formula I are novel compounds, and inthose cases where the active ingredient in the composition is such acompound, the invention also comprises the novel compounds per se.

Compounds included in formula I wherein R₁, R₂ and R₃ are combined asfollows are generically disclosed in the prior art:

    ______________________________________                                        R.sub.1     R.sub.2     R.sub.3                                               ______________________________________                                        H           alkyl       alkyl                                                 H           alkyl       benzyl                                                H           benzyl      alkyl                                                 H           benzyl      benzyl                                                H           H           alkyl                                                 H           H           benzyl                                                alkyl       alkyl       alkyl                                                 alkyl       alkyl       phenyl                                                alkyl       alkyl       phenyl substituted                                                            with alkyl having                                                             1-3 carbon atoms.                                     ______________________________________                                    

The invention includes the compounds per se of formula I excluding thegroups of compounds given in the above table.

In tables below, compounds of the formula I which are known from theprior art are indicated. The invention includes within its scope thosecompounds per se which are included in formula I and which are not knownin the prior art. In particular compounds wherein R₁, R₂ or R₃ are1-adamantyl, 2-adamantyl, or phenyl groups of the formula II wherein theradicals R₄ and R₅ are the same or different and selected from thegroups consisting of halogen, alkoxy having 1-3 carbon atoms,alkoxycarbonyl having 2-3 carbon atoms, and alkylcarbonyl having 2-7carbon atoms, or wherein R₄ and R₅ together form a straight saturatedalkylene chain having 3 or 4 carbon atoms and being bound to adjacentpositions i.e. 2,3- or 3,4- in the phenyl ring, are novel. Furthergroups of novel compounds, which also are included in the scope of theinvention, are indicated in the preferred groups of radicals which areenumerated elsewhere in this specification. Those individual compoundswhich are enumerated in tables below, or which are exemplified inworking examples, and which are not indicated as known in the art, arebelieved to be novel and included within the scope of the invention.

The compounds of the formula I may be hydrolyzed in vivo to givephosphonoformic acid or ionized forms thereof, which are antiviralagents. In a more generalized aspect the invention includes within itsscope the use of all physiologically acceptable compounds (includingphysiologically acceptable salts thereof) of the formula I, wherein R₁,R₂ and R₃, when they are different from H, are any pharmaceuticallyacceptable organic group, which by in vivo hydrolysis is capable offorming phosphonoformic acid or a physiologically acceptable saltthereof in the animal body (i.e. bioprecursors to phosphonoformic acid)for the treatment of virus infections and related ailments, aspreviously described, in animals including man, and pharmaceuticalcompositions containing such compounds.

Phosphonoformic acid and physiologically acceptable salts thereofinhibit viral functions such as polymerases including reversetranscriptase and virus multiplication, and have effects on virusinfections in animal models. The antiviral effects of trisodiumphosphonoformate is described by Helgstrand et. al. Science 201, 819(1978).

An important aspect of the invention is that the radicals R₁, R₂ and R₃in formula I can be chosen in such a way that the compounds of formula Iand physiologically acceptable salts thereof possess more favourablepharmacokinetic properties than phosphonoformic acid and physiologicallyacceptable salts thereof. Such favourable pharmacokinetic propertiesinclude better tissue penetration, better oral absorption and prolongedactivity.

Although the present invention relates broadly to a novel method forselectively combating viral diseases in animals and man, andpharmaceutical preparations to be used in such treatment, it will beparticularly useful in the treatment of herpesvirus infections,influenza virus infections, hepatitis B virus infections.

An especially important area of use for the compositions of the presentinvention is in the treatment of herpes virus infections. Among theherpesviruses may be mentioned Herpes simplex type 1 and 2, varicella(Herpes zoster), virus causing infectious mononucleosis (i.e.Epstein-Barr virus), and cytomegalovirus. Important diseases caused byherpes viruses are herpes dermatitis, (including herpes labialis),herpes genitalis, herpes keratitis and herpes encephalitis. An otherimportant area of use for the compositions of the present invention isin the treatment of infections caused by orthomyxoviruses, i.e.influenza viruses of type A and type B. A further area of use is thetreatment of infections caused by viruses such as hepatitis virus A andhepatitis virus B, papillomaviruses, adenoviruses and poxviruses.

Other possible areas of use for the compositions of the presentinvention are in the treatment of infections caused by picornaviruses,togaviruses including arboviruses, retroviruses (e.g. leucoviruses),arenaviruses, coronaviruses, rhabdoviruses, paramyxoviruses, hepatitisnon A and non B virus, iridoviruses, papovaviruses, parvoviruses,reoviruses, and bunyaviruses.

Illustrative examples of the meanings of the radicals R₁, R₂ and R₃ inthe formula I above are: ##STR8##

The above illustrative examples are intended to illustrate the meaningsof all the radicals R₁, R₂, and R₃ within the boundaries with regard tonumber of carbon atoms which are prescribed for each radical.

Preferred groups of the radicals R₁ and R₂ are:

1. The group consisting of straight and branched alkyl groups containing1-6 carbon atoms, phenyl, and benzyl;

2. The group consisting of straight and branched alkyl groups containing1-4 carbon atoms; phenyl, and benzyl;

3. The group consisting of straight and branched alkyl groups containing1-6 carbon atoms;

4. The group consisting of straight and branched alkyl groups containing1-4 carbon atoms, that is methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, sec-butyl and t-butyl.

5. Phenyl

6. Benzyl

7. 1-adamantyl (novel compounds);

8. 2-adamantyl (novel compounds);

9. monosubstituted phenyl groups: (novel compounds);

10. disubstituted phenyl groups (novel compounds);

11. mono-alkyl substituted phenyl groups (novel compounds)

12. mono-halogen substituted phenyl groups (novel compounds);

13. mono-alkoxy substituted phenyl groups (novel compounds);

14. mono-alkoxycarbonyl substituted phenyl groups (novel compounds);

15. di-alkyl substituted phenyl groups (novel compounds);

16. di-halogen substituted phenyl groups (novel compounds);

17. di-alkoxy substituted phenyl groups (novel compounds);

18. phenyl groups of the formula ##STR9## wherein n is 3 or 4 andwherein the alkylene chain is bound to adjacent positions, i.e. 2,3- or3,4- in the phenyl ring (novel compounds).

19. mono-alkylcarbonyl substituted phenyl groups (novel compounds)

20. cycloalkyl and cycloalkyl-alkyl groups (novel compounds)

Particularly preferred groups of the radicals R₁ and R₂ areunsubstituted, monosubstituted and disubstituted phenyl groups withinthe above formula ##STR10## wherein R₄ and R₅ have the meanings givenabove.

In a preferred embodiment, R₁ and R₂ have the same meaning.

Preferred groups of the radical R₃ are:

1. The groups consisting of straight and branched alkyl groupscontaining 1-8 carbon atoms; phenyl; and benzyl;

2. The group consisting of straight and branched alkyl groups containing1-4 carbon atoms; phenyl; and benzyl;

3. The group consisting of straight and branched alkyl groups containing1-8 carbon atoms;

4. The group consisting of straight and branched alkyl groups containing1-4 carbon atoms, that is methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, sec-butyl and t-butyl.

5. Phenyl

6. Benzyl

7. 1-adamantyl (novel compounds);

8. 2-adamantyl (novel compounds);

9. monosubstituted phenyl groups;

10. disubstituted phenyl groups (novel compounds);

11. mono-alkyl substituted phenyl groups;

12. mono-halogen substituted phenyl groups (novel compounds);

13. mono-alkoxy substituted phenyl groups (novel compounds);

14. mono-alkoxycarbonyl substituted phenyl groups (novel compounds);

15. di-alkyl substituted phenyl groups (novel compounds);

16. di-halogen substituted phenyl groups (novel compounds);

17. di-alkoxy substituted phenyl groups (novel compounds);

18. phenyl groups of the formula ##STR11## wherein n is 3 or 4 andwherein the alkylene chain is bound to adjacent positions, i.e. 2,3- or3,4- in the phenyl ring (novel compounds).

19. mono-alkylcarbonyl substituted phenyl groups (novel compounds);

20. cycloalkyl and cycloalkyl-alkyl groups (novel compounds);

Particularly preferred groups of the radical R₃ are unsubstituted,monosubstituted and disubstituted phenyl groups within the above formula##STR12## wherein R₄ and R₅ have the meanings given above.

Preferred combinations of R₁, R₂, and R₃ are:

1. R₁ and R₂ are selected from the group consisting of straight andbranched alkyl groups containing 1-6 carbon atoms, phenyl, and benzyl;and R₃ is selected from the group consisting of straight and branchedalkyl groups containing 1-6 carbon atoms, phenyl, and benzyl;

2. R₁, R₂, and R₃ are selected from the group consisting of straight andbranched alkyl groups containing 1-4 carbon atoms; phenyl; and benzyl;

3. R₁ and R₂ are selected from the group consisting of straight andbranched alkyl groups containing 1-6 carbon atoms; and R₃ is selectedfrom the group consisting of straight and branched alkyl groupscontaining 1-8 carbon atoms;

4. R₁, R₂, and R₃ are selected from the group consisting of straight andbranched alkyl groups containing 1-4 carbon atoms;

5. R₁, R₂, and R₃ are benzyl (novel compound);

6. in each of the groups 1-4 above, R₁ having the same meaning as R₂ ;

7. R₁ and R₂ are selected from the group consisting of alkyl groupscontaining 1-4 carbon atoms and R₃ is selected from the group consistingof an unsubstituted, monosubstituted or disubstituted phenyl groupwithin the formula ##STR13## wherein R₄ and R₅ have the meanings givenabove (novel compounds except where R₃ is mono-alkyl substitutedphenyl);

8. R₁ is an alkyl group containing 1-4 carbon atoms, R₂ and R₃ are thesame or different and are selected from the group consisting ofunsubstituted, monosubstituted or disubstituted phenyl groups within theformula ##STR14## wherein R₄ and R₅ have the meanings given above (novelcompounds);

9. R₁ and R₂ are the same or different and are selected from the groupconsisting of an unsubstituted, monosubstituted or disubstituted phenylgroup within the formula ##STR15## wherein R₄ and R₅ have the meaningsgiven above, and R₃ is an alkyl group containing 1-4 carbon atoms (novelcompounds);

10. R₁ and R₂ are the same or different and are selected from the groupconsisting of alkyl groups containing 1-4 carbon atoms, and R₃ isselected from the group consisting of 1-adamantyl and 2-adamantyl (novelcompounds);

11. R₁, R₂, and R₃ are selected from the group consisting of straightand branched alkyl groups containing 1-4 carbon atoms, benzyl,unsubstituted, monosubstituted or disubstituted phenyl groups within theformula ##STR16## wherein R₄ and R₅ have the meanings given above;1-adamantyl; and 2-adamantyl, whereby at least one of the groups R₁, R₂,and R₃ is not alkyl or benzyl.

12. R₁ and R₂ are selected from the group consisting of straight andbranched alkyl groups containing 1-4 carbon atoms; and unsubstituted,monosubstituted or disubstituted phenyl groups with the formula##STR17## wherein R₄ and R₅ have the meanings given above; and R₃ isselected from the group consisting of 1-adamantyl and 2-adamantyl (novelcompounds);

13. R₁ and R₂ are selected from the group consisting of straight andbranched alkyl groups containing 1-4 carbon atoms; and unsubstituted,monosubstituted or disubstituted phenyl groups within the formula##STR18## wherein R₄ and R₅ have the meanings given above; and R₃ isbenzyl;

14. in each of the groups 7, 9, 10, 11, 12, and 13 above, R₁ having thesame meaning as R₂.

15. R₁ and R₂ are hydrogen and R₃ is selected from the group consistingof straight and branched alkyl groups containing 1-8 carbon atoms; andbenzyl;

16. R₁ and R₂ are hydrogen and R₃ is selected from the group consistingof straight and branched alkyl groups containing 1-4 carbon atoms; andbenzyl;

17. R₁ and R₂ are hydrogen and R₃ is selected from the group consistingof straight and branched alkyl groups containing 1-8 carbon atoms;

18. R₁ and R₂ are hydrogen and R₃ is selected from the group consistingof straight and branched alkyl groups containing 1-4 carbon atoms, thatis methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, andt-butyl;

19. R₁ and R₂ are hydrogen and R₃ is benzyl;

20. R₁ and R₂ are hydrogen and R₃ is 1-adamantyl (novel compound);

21. R₁ and R₂ are hydrogen and R₃ is 2-adamantyl (novel compound);

22. R₁ is H, R₂ is selected from the group consisting of straight andbranched alkyl groups containing 1-6 carbon atoms; and benzyl; and R₃ isselected from the group consisting of straight and branched alkyl groupscontaining 1-8 carbon atoms; phenyl; and benzyl;

23. R₁ is H, R₂ and R₃ are selected from the group consisting ofstraight and branched alkyl groups containing 1-4 carbon atoms; andbenzyl;

24. R₁ is H, R₂ is selected from the group consisting of straight andbranched alkyl groups containing 1-6 carbon atoms; and R₃ is selectedfrom the group consisting of straight and branched alkyl groupscontaining 1-8 carbon atoms;

25. R₁ is H, and R₂ and R₃ are selected from the group consisting ofstraight and branched alkyl groups containing 1-4 carbon atoms;

26. R₁ is H, and R₂ and R₃ are benzyl (novel compound);

27. R₁ is H, R₂ is monosubstituted or disubstituted phenyl groups withinthe formula ##STR19## wherein R₄ and R₅ have the meanings given aboveand R₃ is selected from the group consisting of straight and branchedalkyl groups containing 1-8 carbon atoms; and benzyl (novel compounds);

28. R₁ is H, R₂ is selected from the group consisting of straight andbranched alkyl groups containing 1-6 carbon atoms; benzyl;unsubstituted, monosubstituted and disubstituted phenyl groups withinthe above formula ##STR20## wherein R₄ and R₅ have the meanings givenabove; 1-adamantyl; and 2-adamantyl; and R₃ is selected from the groupconsisting of 1-adamantyl and 2-adamantyl (novel compounds);

29. R₁ is H, R₂ is 1-adamantyl or 2-adamantyl, and R₃ is selected fromthe group consisting of straight and branched alkyl groups containing1-6 carbon atoms; benzyl; unsubstituted, monosubstituted anddisubstituted phenyl groups within the above formula ##STR21## whereinR₄ and R₅ have the meanings given above; 1-adamantyl and 2-adamantyl(novel compounds);

30. R₁ is H, R₂ is selected from the group consisting of straight andbranched alkyl groups containing 1-6 carbon atoms and benzyl; and R₃ isselected from the group consisting of monosubstituted or disubstitutedphenyl groups within the formula ##STR22## where R₄ and R₅ have themeanings given above;

31. R₁ and R₃ are H and R₂ is selected from the group consisting ofstraight and branched alkyl groups containing 1-6 carbon atoms; andbenzyl;

32. R₁ and R₃ are H and R₂ is selected from the group consisting ofstraight and branched alkyl groups containing 1-4 carbon atoms andbenzyl;

33. R₁ and R₃ are H and R₂ is selected from the group consisting ofstraight and branched alkyl groups containing 1-6 carbon atoms;

34. R₁ and R₃ are H and R₂ is selected from the group consisting ofstraight and branched alkyl groups containing 1-4 carbon atoms, that ismethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl andt-butyl;

35. R₁ and R₃ are H and R₂ is benzyl;

36. R₁ and R₃ are H and R₂ is 1-adamantyl (novel compound);

37. R₁ and R₃ are H and R₂ is 2-adamantyl (novel compound);

38. Compounds of the formula I wherein R₁ and R₂ are hydrogen.

39. Compounds of the formula I wherein R₁ is hydrogen.

40. Compounds of the formula I wherein R₁ and R₃ are hydrogen.

Examples of compounds of the invention are given in the following table.In the right margin it is indicated whether the compound has beenspecifically disclosed in the prior art. All the other compounds arebelieved to be novel, and thus constitute a further aspect of theinvention.

    __________________________________________________________________________    R.sub.1     R.sub.2    R.sub.3                                                __________________________________________________________________________    H           H          CH.sub.3      prior art                                H           H          C.sub.2 H.sub.5                                                                             prior art                                H           H          n-C.sub.3 H.sub.7                                      H           H          i-C.sub.3 H.sub.7                                      H           H          n-C.sub.4 H.sub.9                                      H           H          sec.-C.sub.4 H.sub.9                                   H           H          i-C.sub.4 H.sub.9                                                                           prior art                                H           H          tert.-C.sub.4 H.sub.9                                  H           H          n-C.sub.5 H.sub.11                                                                          prior art                                H           H          n-C.sub.6 H.sub.13                                                                          prior art                                H           H          n-C.sub.7 H.sub.15                                     H           H          n-C.sub.8 H.sub.17                                     H           H          benzyl        prior art                                H           H          1-adamantyl                                            H           H          2-adamantyl                                            H           CH.sub.3   CH.sub.3      prior art for R.sub.1 = Na               H           CH.sub.3   C.sub.2 H.sub.5                                        H           CH.sub.3   n-C.sub.3 H.sub.7                                      H           CH.sub.3   i-C.sub.3 H.sub.7                                                                           prior art for R.sub.1 = Na               H           CH.sub.3   n-C.sub.4 H.sub.9                                                                           prior art for R.sub.1                                                         = 1/2 Ba.sup.2+                          H           CH.sub.3   n-C.sub.5 H.sub.11                                     H           CH.sub.3   n-C.sub.6 H.sub.13                                                                          prior art for R.sub.1 = Na               H           CH.sub.3   n-C.sub.7 H.sub. 15                                    H           CH.sub.3   n-C.sub.8 H.sub.17                                     H           CH.sub.3   phenyl                                                 H           CH.sub.3   benzyl        prior art                                H           C.sub.2 H.sub.5                                                                          CH.sub.3      prior art for R.sub.1 = Na               H           C.sub.2 H.sub.5                                                                          C.sub.2 H.sub.5                                        H           C.sub.2 H.sub.5                                                                          n-C.sub.3 H.sub.7                                      H           C.sub.2 H.sub.5                                                                          i-C.sub.3 H.sub.7                                      H           C.sub.2 H.sub.5                                                                          n-C.sub.4 H.sub.9                                      H           C.sub.2 H.sub.5                                                                          sec-C.sub.4 H.sub.9                                    H           C.sub.2 H.sub.5                                                                          i-C.sub.4 H.sub.9                                      H           C.sub.2 H.sub.5                                                                          tert-C.sub.4 H.sub.9                                   H           C.sub.2 H.sub.9                                                                          n-C.sub.5 H.sub.11                                     H           C.sub.2 H.sub.5                                                                          n-C.sub.6 H.sub.13                                     H           C.sub.2 H.sub.5                                                                          n-C.sub.7 H.sub.15                                     H           C.sub.2 H.sub.5                                                                          n-C.sub.8 H.sub.17                                     H           C.sub.2 H.sub.5                                                                          phenyl                                                 H           C.sub.2 H.sub.5                                                                          benzyl        prior art for R.sub.1 = Na               H           n-C.sub.3 H.sub.7                                                                        CH.sub.3                                               H           n-C.sub.3 H.sub.7                                                                        C.sub.2 H.sub.5                                                                             prior art for R.sub.1 = Na               H           n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                      H           n-C.sub.3 H.sub.7                                                                        i-C.sub.3 H.sub.7                                      H           n-C.sub.3 H.sub.7                                                                        n-C.sub.4 H.sub.9                                      H           n-C.sub.3 H.sub.7                                                                        n-C.sub.5 H.sub.11                                     H           n-C.sub.3 H.sub.7                                                                        n-C.sub.6 H.sub.13                                     H           i-C.sub.3 H.sub.7                                                                        C.sub.2 H.sub.5                                        H           n-C.sub.4 H.sub.9                                                                        CH.sub.3                                               H           n-C.sub.4 H.sub.9                                                                        C.sub.2 H.sub.5                                                                             prior art                                H           n-C.sub.4 H.sub.9                                                                        n-C.sub.3 H.sub.7                                      H           n-C.sub.4 H.sub.9                                                                        i-C.sub.3 H.sub.7                                      H           n-C.sub.4 H.sub.9                                                                        n-C.sub.4 H.sub.9                                      H           n-C.sub.4 H.sub.9                                                                        n-C.sub.5 H.sub.11                                     H           n-C.sub.4 H.sub.9                                                                        phenyl                                                 H           n-C.sub.4 H.sub.9                                                                        benzyl                                                 H           n-C.sub.5 H.sub.11                                                                       CH.sub.3                                               H           n-C.sub.5 H.sub.11                                                                       C.sub.2 H.sub.5                                        H           n-C.sub.5 H.sub.11                                                                       n-C.sub.3 H.sub.7                                      H           n-C.sub.5 H.sub.11                                                                       phenyl                                                 H           n-C.sub.6 H.sub.13                                                                       CH.sub.3                                               H           n-C.sub.6 H.sub.13                                                                       C.sub.2 H.sub.5                                        H           n-C.sub.7 H.sub.15                                                                       CH.sub.3                                               H           n-C.sub.7 H.sub.15                                                                       C.sub.2 H.sub.5                                        H           n-C.sub.8 H.sub.17                                                                       CH.sub.3                                               H           n-C.sub.8 H.sub.17                                                                       C.sub.2 H.sub.5                                        H           phenyl     CH.sub.3                                               H           phenyl     C.sub.2 H.sub.5                                        H           benzyl     CH.sub.3      prior art for R.sub.1 =  Na              H           benzyl     C.sub.2 H.sub.5                                        H           phenyl     1-adamantyl                                            H           phenyl     2-adamantyl                                            H           4-chlorophenyl                                                                           1-adamantanyl                                          H           4-chlorophenyl                                                                           2-adamantanyl                                          H           4-chlorophenyl                                                                            ##STR23##                                             H           4-methoxyphenyl                                                                          1-adamantyl                                            H           4-methoxyphenyl                                                                          2-adamantyl                                            H           4-methoxyphenyl                                                                           ##STR24##                                             H           4-methylphenyl                                                                           1-adamantyl                                            H           4-methylphenyl                                                                           2-adamantyl                                            H           1-adamantyl                                                                              2-chlorophenyl                                         H           1-adamantyl                                                                              2,3-chlorophenyl                                       H           1-adamantyl                                                                              2,4-chlorophenyl                                       H           1-adamantyl                                                                              4-chlorophenyl                                         H           1-adamantyl                                                                              4-methoxyphenyl                                        H           1-adamantyl                                                                              4-methylphenyl                                         H           1-adamantyl                                                                              4-ethoxycarbonylphenyl                                 H           1-adamantyl                                                                              1-adamantyl                                            H           2-adamantyl                                                                              4-chlorophenyl                                         H           2-adamantyl                                                                              3,4-dichlorophenyl                                     H           2-adamantyl                                                                              4-methoxyphenyl                                        H           2-adamantyl                                                                              4-methylphenyl                                         H           2-adamantyl                                                                              4-ethoxycarbonylphenyl                                 H           2-adamantyl                                                                              2-adamantyl                                            CH.sub.3    CH.sub.3   CH.sub.3      prior art                                CH.sub.3    CH.sub.3   C.sub.2 H.sub.5                                                                             prior art                                CH.sub.3    CH.sub.3   n-C.sub.3 H.sub.7                                      CH.sub.3    CH.sub.3   i-C.sub.3 H.sub.7                                      CH.sub.3    CH.sub.3   n-C.sub.4 H.sub.9                                      CH.sub.3    CH.sub.3   n-C.sub.5 H.sub.11                                     CH.sub.3    CH.sub.3   n-C.sub.6 H.sub.13                                     CH.sub.3    CH.sub.3   n-C.sub.7 H.sub.15                                     CH.sub.3    CH.sub.3   n-C.sub.8 H.sub.17                                     CH.sub.3    CH.sub.3   phenyl                                                 CH.sub.3    CH.sub.3   benzyl        prior art                                C.sub.2 H.sub.5                                                                           C.sub.2 H.sub.5                                                                          CH.sub.3      prior art                                C.sub.2 H.sub. 5                                                                          C.sub.2 H.sub.5                                                                          C.sub.2 H.sub.5                                                                             prior art                                C.sub.2 H.sub.5                                                                           C.sub.2 H.sub.5                                                                          n-C.sub.3 H.sub.7                                      C.sub.2 H.sub.5                                                                           C.sub.2 H.sub.5                                                                          i-C.sub.3 H.sub.7                                      C.sub.2 H.sub.5                                                                           C.sub.2 H.sub.5                                                                          n-C.sub.4 H.sub.9                                      C.sub.2 H.sub.5                                                                           4-methoxyphenyl                                                                          C.sub.2 H.sub.5                                        C.sub.2 H.sub.5                                                                           C.sub.2 H.sub.5                                                                          sec-C.sub.4 H.sub.9                                    C.sub.2 H.sub.5                                                                           C.sub.2 H.sub.5                                                                          i-C.sub.4 H.sub.9                                      C.sub.2 H.sub.5                                                                           C.sub.2 H.sub.5                                                                          tert.-C.sub.4 H.sub.9                                  C.sub.2 H.sub.5                                                                           C.sub.2 H.sub.5                                                                          n-C.sub.5 H.sub.11                                     C.sub.2 H.sub.5                                                                           C.sub.2 H.sub.5                                                                          n-C.sub.6 H.sub.13                                     C.sub.2 H.sub.5                                                                           C.sub.2 H.sub.5                                                                          n-C.sub.7 H.sub.15                                     C.sub.2 H.sub.5                                                                           C.sub.2 H.sub.5                                                                          n-C.sub.8 H.sub.17                                     C.sub.2 H.sub.5                                                                           C.sub.2 H.sub.5                                                                          phenyl                                                 C.sub.2 H.sub.5                                                                           C.sub.2 H.sub.5                                                                          benzyl                                                 n-C.sub.3 H.sub.7                                                                         n-C.sub.3 H.sub.7                                                                        CH.sub.3                                               n-C.sub.3 H.sub.7                                                                         n-C.sub.3 H.sub.7                                                                        C.sub.2 H.sub.5                                                                             prior art                                n-C.sub.3 H.sub.7                                                                         n-C.sub.3 H.sub.7                                                                        n-C.sub.3 H.sub.7                                      n-C.sub.3 H.sub.7                                                                         n-C.sub.3 H.sub.7                                                                        i-C.sub.3 H.sub.7                                      n-C.sub.3 H.sub.7                                                                         n-C.sub.3 H.sub.7                                                                        n-C.sub.4 H.sub.9                                      n-C.sub.3 H.sub.7                                                                         n-C.sub.3 H.sub.7                                                                        n-C.sub.5 H.sub.11                                     n-C.sub.3 H.sub.7                                                                         n-C.sub.3 H.sub.7                                                                        n-C.sub.6 H.sub.13                                     i-C.sub.3 H.sub.7                                                                         i-C.sub.3 H.sub.7                                                                        C.sub.2 H.sub.5                                                                             prior art                                n-C.sub.4 H.sub.9                                                                         n-C.sub.4 H.sub.9                                                                        CH.sub.3                                               n-C.sub.4 H.sub.9                                                                         n-C.sub.4 H.sub.9                                                                        C.sub.2 H.sub.5                                                                             prior art                                n-C.sub.4 H.sub.9                                                                         n-C.sub.4 H.sub.9                                                                        n-C.sub.3 H.sub.7                                      n-C.sub.4 H.sub.9                                                                         n-C.sub.4 H.sub.9                                                                        i-C.sub.3 H.sub.7                                      n-C.sub.4 H.sub.9                                                                         n-C.sub.4 H.sub.9                                                                        n-C.sub.4 H.sub.9                                      n-C.sub.4 H.sub.9                                                                         n-C.sub.4 H.sub.9                                                                        n-C.sub.5 H.sub.11                                     n-C.sub.4 H.sub.9                                                                         n-C.sub.4 H.sub.9                                                                        phenyl        prior art                                n-C.sub.4 H.sub.9                                                                         n-C.sub.4 H.sub.9                                                                        benzyl                                                 n-C.sub.5 H.sub.11                                                                        n-C.sub.5 H.sub.11                                                                       CH.sub.3                                               n-C.sub.5 H.sub.11                                                                        n-C.sub.5 H.sub.11                                                                       C.sub.2 H.sub.5                                        n-C.sub.5 H.sub.11                                                                        n-C.sub.5 H.sub.11                                                                       n-C.sub.3 H.sub.7                                      n-C.sub.5 H.sub.11                                                                        n-C.sub.5 H.sub.11                                                                       phenyl                                                 n-C.sub.6 H.sub.13                                                                        n-C.sub.6 H.sub.13                                                                       CH.sub. 3                                              n-C.sub.6 H.sub.13                                                                        n-C.sub.6 H.sub.13                                                                       C.sub.2 H.sub.5                                        n-C.sub.7 H.sub.15                                                                        n-C.sub.7 H.sub.15                                                                       CH.sub.3                                               n-C.sub.7 H.sub.15                                                                        n-C.sub.7 H.sub.15                                                                       C.sub.2 H.sub.5                                        n-C.sub.8 H.sub.17                                                                        n-C.sub.8 H.sub.17                                                                       CH.sub.3                                               n-C.sub.8 H.sub.17                                                                        n-C.sub.8 H.sub.17                                                                       C.sub.2 H.sub.5                                        phenyl      phenyl     CH.sub.3                                               phenyl      phenyl     C.sub.2 H.sub.5                                                                             prior art                                phenyl      phenyl     phenyl                                                 benzyl      benzyl     CH.sub.3                                               benzyl      benzyl     C.sub.2 H.sub.5                                        4-methylphenyl                                                                            4-methylphenyl                                                                           ethyl                                                  4-methoxyphenyl                                                                           ethyl      phenyl                                                 4-chlorophenyl                                                                            ethyl      phenyl                                                 3,4-dichlorophenyl                                                                        ethyl      phenyl                                                 methyl      methyl     4-methylphenyl                                         methyl      methyl     3,4-dichlorophenyl                                     methyl      methyl     2-adamantyl                                            ethyl       ethyl      4-methoxyphenyl                                        ethyl       ethyl      4-chlorophenyl                                         ethyl       ethyl      4-ethoxycarbonylphenyl                                 ethyl       ethyl                                                                                     ##STR25##                                             2,3-dichlorophenyl                                                                        phenyl     ethyl                                                  methyl      methyl     2,6-dimethylphenyl                                     2-methyl-4-chlorophenyl                                                                   ethyl      phenyl                                                 2-adamantyl methyl     ethyl                                                  1-adamantyl methyl     methyl                                                 H           CH.sub.3   H             (prior art)                              H           C.sub.2 H.sub.5                                                                          H             (prior art)                              H           n-C.sub.3 H.sub.7                                                                        H                                                      H           i-C.sub.3 H.sub.7                                                                        H                                                      H           n-C.sub.4 H.sub.9                                                                        H             (prior art)                              H           iso-C.sub.4 H.sub.9                                                                      H                                                      H           sec-C.sub.4 H.sub.9                                                                      H                                                      H           tert-C.sub.4 H.sub.9                                                                     H                                                      H           n-C.sub.5 H.sub.11                                                                       H                                                      H           n-C.sub. 6 H.sub.13                                                                      H                                                      H           benzyl     H             (prior art)                              H           1-adamantyl                                                                              H                                                      H           2-adamantyl                                                                              H                                                      __________________________________________________________________________

Particularly preferred compounds are:

    ______________________________________                                        R.sub.1  R.sub.2     R.sub.3       Code                                       ______________________________________                                        H        H           C.sub.2 H.sub.5                                                                             VIS 210                                    H        H           n-C.sub.4 H.sub.9                                                                           VIS 418                                    H        H           benzyl        VIS 409                                    H        H           i-C.sub.3 H.sub.7                                                                           VIS 420                                    H        H           2-adamantyl   VIS 131                                    H        C.sub.2 H.sub.5                                                                           C.sub.2 H.sub.5                                                                             VIS 414                                    H        n-C.sub.4 H.sub.9                                                                         CH.sub.3      VIS 047                                    H        CH.sub.3    benzyl        VIS 406                                    H        phenyl      C.sub.2 H.sub.5                                                                             VIS 036                                    C.sub.2 H.sub.5                                                                        C.sub.2 H.sub.5                                                                           C.sub.2 H.sub.5                                                                             EHB 783                                                                       (prior art)                                C.sub.2 H.sub.5                                                                        C.sub.2 H.sub.5                                                                           CH.sub.3      VIS 224                                                                       (prior art)                                n-C.sub.4 H.sub.9                                                                      n-C.sub.4 H.sub.9                                                                         CH.sub.3      VIS 046                                    CH.sub.3 CH.sub.3    n-C.sub.4 H.sub.9                                                                           VIS 415                                    CH.sub.3 CH.sub.3    phenyl        VIS 416                                    CH.sub.3 CH.sub.3    benzyl        VIS 405                                    phenyl   phenyl      C.sub.2 H.sub.5                                                                             VIS 035                                                                       (prior art)                                benzyl   benzyl      C.sub.2 H.sub.5                                                                             VIS 201                                    CH.sub.3 CH.sub.3    i-C.sub.3 H.sub.7                                                                           VIS 419                                    4-methoxy-                                                                             ethyl       phenyl        VIS 057                                    phenyl                                                                        4-chloro-                                                                              ethyl       phenyl        VIS 061                                    phenyl                                                                        3,4-dichloro-                                                                          ethyl       phenyl        VIS 062                                    phenyl                                                                        methyl   methyl      4-methylphenyl                                                                              VIS 128                                    methyl   methyl      3,4-dichloro- VIS 134                                                         phenyl                                                   methyl   methyl      2-adamantyl   VIS 129                                    ethyl    ethyl       4-methoxyphenyl                                                                             VIS 236                                    ethyl    ethyl       4-chlorophenyl                                                                              VIS 237                                    CH.sub.3 CH.sub.3    cyclo-C.sub.6 H.sub.11                                                                      VIS 137                                    CH.sub.3 CH.sub.3    CH.sub.2 --cyclo-C.sub.5 H.sub.9                                                            VIS 140                                    CH.sub.3 1-adamantyl CH.sub.3      VIS 077                                    C.sub.2 H.sub.5                                                                        C.sub.2 H.sub.5                                                                           4-ethoxycarbonyl-                                                                           VIS 241                                                         phenyl                                                   CH.sub.3 CH.sub.3    4-ethoxycarbonyl-                                                                           VIS 243                                                         phenyl                                                   C.sub.2 H.sub.5                                                                        2,6-dimethyl-                                                                             CH.sub.3      VIS 435                                             phenyl                                                               C.sub.2 H.sub.5                                                                        5-indanyl   CH.sub.3      VIS 436                                    CH.sub.3 4-acetylphenyl                                                                            CH.sub.3      VIS 072                                    H        H           Cyclo-C.sub.6 H.sub.11                                                                      VIS 138                                    H        H           CH.sub.2 --cyclo-C.sub.6 H.sub.11                                                           VIS 141                                    H        1-adamantyl CH.sub.3      VIS 079                                    H        5-indanyl   CH.sub.3      VIS 441                                    H        2,6-dimethyl-                                                                             CH.sub.3      VIS 439                                             phenyl                                                               H        1-adamantyl H             VIS 078                                    H        CH.sub.3    H             VIS 018                                                                       (prior art)                                ______________________________________                                    

and physiologically acceptable salts thereof.

Salts of the active substances

Physiologically acceptable salts of those active substances of theformula I which form salts are prepared by methods known in the art asillustrated in the following.

Examples of metal salts which can be prepared are salts containing Li,Na, K, Ca, Mg, Zn, Mn and Ba. A less soluble metal salt can beprecipitated from a solution of a more soluble salt by addition of asuitable metal compound. Thus for examples, Ca, Ba, Zn, Mg, and Mn saltsof the active substances can be prepared from sodium salts thereof. Themetal ion of a metal salt of the active substances can be exchanged byhydrogen ions, other metal ions, ammonium ion and ammonium ionssubstituted by one or more organic radicals by using a cation exchanger.

Examples of other useful salts which can be prepared in this way are thesalts of the formula ##STR26## in which formula R₁ R₂ and R₃ have thesame meaning as above, n is 1 or 2, and X is a salt-forming componentsuch as NH₃, CH₃ NH₂, C₂ H₅ NH₂, C₃ H₇ NH₂, C₄ H₉ NH₂, C₅ H₁₁ NH₂, C₆H₁₃ NH₂, (CH₃)₂ NH, (C₂ H₅)₂ NH, (C₃ H₇)₂ NH, (C₄ H₉)₂ NH, (C₅ H₁₁)₂ NH,(C₆ H₁₃)₂ NH, (CH₃)₃ N, (C₂ H₅)₃ N, (C₃ H₇)₃ N, (C₄ H₉)₃ N, (C₅ H₁₁)₃ N,(C₆ H₁₃)₃ N, C₆ H₅ CH₂ NH₂, HOCH₂ CH₂ NH₂, (HOCH₂ CH₂)₂ NH, (HOCH₂ CH₂)₃N, C₂ H₅ NH(CH₂ CH₂ OH), C₂ H₅ N (CH₂ CH₂ OH)₂, (HOH₂ C)₃ CNH₂ and##STR27##

Further examples of other useful salts which can be prepared by the ionexchange technique are quaternary ammonium salts of the activesubstances, i.e. salts in which the hydrogens in the active substances(structural formula I) have been substituted with quarternary ammoniumions such as (CH₃)₄ N, (C₃ H₇)₄ N, (C₄ H₉)₄ N, (C₅ H₁₁)₄ N, (C₆ H₁₃)₄ Nand C₂ H₅ N(CH₂ CH₂ OH)₃. Lipophilic salts of this type can also beprepared by mixing a salt of the active substances with a quaternaryammonium salt in water and extracting out the resulting quaternaryammonium salt of the active substances with an organic solvent such asdichloromethane, chloroform, ethyl acetate and methyl isobutyl ketone.

The compounds utilized within the invention may be formulated for use inhuman and veterinary medicine for therapeutic and prophylactic use. Thecompounds may be used in the form of a physiologically acceptable salt.Suitable salts are e.g. amine salts, e.g. dimethylamine andtriethylamine salt, ammonium salt tetrabutylammonium salt,cyclohexylamine salt, dicyclohexylamine salt; and metal salts, e.g.mono-, and disodium salt, mono- and dipotassium salt, magnesium salt,calcium salt and zinc salt.

The compounds utilized within the invention are particularly useful forsystemic treatment of virus infections, by oral administration or byinjection. In comparison with phosphonoformic acid, they are generallymore stable in acid solutions, and are thus less readily decomposed inthe stomach.

In comparison with phosphonoformic acid the compounds of the presentinvention are more lipophilic and are thus more suitable to treat virusinfections in organs for which penetration through lipid barriers are ofimportance.

In clinical practice the compound will normally be administeredtopically, orally, intranasally, by injection or by inhalation in theform of a pharmaceutical preparation comprising the active ingredient inthe form of the original compound or optionally in the form ofpharmaceutically acceptable salt thereof, in association with apharmaceutically accaptable carrier which may be a solid, semi-solid orliquid diluent or an ingestible capsule, and such preparations comprisea further aspect of the invention. The compound may also be used withoutcarrier material. As examples of pharmaceutical preparations may bementioned tablets, drops such as nasal and eye drops, preparations fortopical application such as ointments, jellies, creams and suspensions,aerosols for inhalation, nasal spray, liposomes, etc. Usually the activesubstance will comprise between 0.05 and 99, or between 0.1 and 99% byweight of the preparation, for example between 0.5 and 20% forpreparations intended for injection and between 0.1 and 50% forpreparations intended for oral administration.

To produce pharmaceutical preparations in the form of dosage units fororal application containing a compound of the invention the activeingredient may be mixed with a solid, pulverulent carrier, for examplelactose, saccharose, sorbitol, mannitol, a starch such as potato starch,corn starch, amylopectin, laminaria powder or citrus pulp powder, acellulose derivative or gelatine and also may include lubricants such asmagnesium or calcium stearate or a Carbowax® or other polyethyleneglycol waxes and compressed to form tablets or cores for dragees. Ifdragees are required, the cores may be coated for example withconcentrated sugar solutions which may contain gum arabic, talc and/ortitainium dioxide, or alternatively with a film forming agent dissolvedin easily volatile organic solvents or mixtures of organic solvents.Dyestuffs can be added to these coatings, for example, to distinguishbetween different contents of active substance. For the preparation ofsoft gelatine capsules consisting of gelatine and, for example, glycerolas a plasticizer, or similar closed capsules, the active substance maybe admixed with a Carbowax® or a suitable oil as e.g. sesam oil, oliveoil, or arachis oil. Hard gelatine capsules may contain granulates ofthe active substance with solid, pulverulent carriers such as lactose,saccharose, sorbitol, mannitol, starches (for example potato starch,corn starch or amylopectin), cellulose derivatives or gelatine, and mayalso include magnesium stearate or stearic acid as lubricants.

By using several layers of the active drug, separated by slowlydissolving coatings sustained release tablets are obtained. Another wayof preparing sustained release tablets is to divide the dose of theactive drug into granules with coatings of different thicknesses andcompress the granules into tablets together with the carrier substance.The active substance can also be incorporated in slowly dissolvingtablets made for instance of fat and wax substances or evenlydistributed in a tablet of an insoluble substance such as aphysiologically inert plastic substance.

In order to obtain dosage units of oral preparations--tablets, capsules,etc.--which are designed so as to prevent release of and possibledecomposition of the active substance in the gastric juice, the tablets,dragees etc. may be enteric coated, that is provided with a layer of agastric juice resistant enteric film or coating having such propertiesthat it is not dissolved at the acidic pH in the gastric juice. Thus,the active substance will not be released until the preparation reachesthe intestines. As examples of such known enteric coatings may bementioned cellulose acetate phtalate, hydroxypropylmethylcellulosephtalates such as those sold under the trade names HP 55 and HP 50, andEudragit®L and Eudragit®S.

Effervescent powders are prepared by mixing the active ingredient withnon-toxic carbonates or hydrogen carbonates of e.g. sodium, potassium orcalcium, such as calcium carbonate, potassium carbonate and potassiumhydrogen carbonate, solid, non-toxic acids such as tartaric acid,ascorbic acid, and citric acid, and for example aroma.

Liquid preparations for oral application may be in the form of elixirs,syrups or suspensions, for example solutions containing from about 0.1%to 20% by weight of active substance, sugar and a mixture or ethanol,water, glycerol, propylene glycol and optionally aroma, saccharineand/or carboxymethylcellulose as a dispersing agent.

For parenteral application by injection preparations may comprise anaqueous suspension of the active compounds according to the invention,desirably in a concentration of 0.5-10%, and optionally also astabilizing agent and/or buffer substances in aqueous solution. Dosageunits of the solution may advantageously be enclosed in ampoules.

For topical application, especially for the treatment of herpes virusinfections on skin, genitals and in mouth and eyes the preparations aresuitably in the form of a solution, ointment, gel, suspension, cream orthe like. The amount of active substance may vary, for example between0.05-20% by weight of the preparation. Such preparations for topicalapplication may be prepared in known manner by mixing the activesubstance with known carrier materials such as isopropanol, glycerol,paraffine, stearyl alcohol, polyethylene glycol, etc. Thepharmaceutically acceptable carrier may also include a known chemicalabsorption promotor. Examples of absorption promoters are e.g.dimethylacetamide (U.S. Pat. No. 3,472,931), trichloroethanol ortrifluoromethanol (U.S. Pat. No. 3,891,757), certain alcohols andmixtures thereof (British Pat. No. 1,001,949). A carrier material fortopical application to unbroken skin is also described in the Britishpatent specification No. 1,464,975, which discloses a carrier materialconsisting of a solvent comprising 40-70% (v/v) isopropanol and 0-60%(v/v) glycerol, the balance, if any, being an inert constituent of adiluent not exceeding 40% of the total volume of solvent.

The dosage at which the active ingredients are administered may varywithin a wide range and will depend on various factors such as forexample the severity of the infection, the age of the patient, etc., andmay have to be individually adjusted. As a possible range for the amountof the active substance which may be administered per day may bementioned from about 0.1 mg to about 2000 mg or from about 1 mg to about2000 mg, or preferably from 1 mg to about 2000 mg for topicaladministration, from 50 mg to about 2000 mg or from 100 to 1000 mg fororal administration and from 10 mg to about 2000 mg or from 50 to 500 mgfor injection. In severe cases it may be necessary to increase thesedoses 5-fold to 10-fold. In less severe cases it may be sufficient touse up to 500 or 1000 mg.

The pharmaceutical compositions containing the active ingredients maysuitably be formulated so that they provide doses within these rangeseither as single dosage units or as multiple dosage units.

Thus, it has been found according to the invention that the abovecompounds, and the physiologically acceptable salts thereof can be usedto selectively inhibit the multiplication of viruses and the compoundsand physiologically acceptable salts thereof are therefore useful intherapeutic and/or propylactic treatment of virus infections asdescribed above.

Preparation of the active substances

Reference to "meaning given above" for R₁, R₂ and R₃ as used belowrefers to the definitions given in formula I.

The hydroxycarbonylphosphoric acid triesters may be prepared by knownmethods for example as described in Houben-Weyl, Methoden derOrganischen Chemie, Auflage 4, Band XII, Teil 1, OrganischePhosphorverbiindungen, p. 433-463. Examples of such methods are thefollowing.

A. Reacting formic acid ester compounds with phosphite triestersaccording to the formula: ##STR28## wherein R₁ and R₃ have the meaninggiven above except that R₁ must not be phenyl or substituted phenyl. R₁₀is a leaving group suitable for Arbuzov type reactions, such as Cl, Br,I, sulphonate, carboxylate, alkoxide.

Preferably the reaction is performed at 0° to 150° for 1 to 50 hours.

B. Reacting formic acid ester compounds with phosphite triestersaccording to the formula: ##STR29## wherein R₁, R₃ and R₁₀ have themeaning given above. R₁₁ may be an alkyl, a cycloalkyl, acycloalkyl-alkyl, a benzyl, an adamantyl or any phosphite esterifyinggroup suitable for participation in Arbuzov type reactions.

Preferably the reaction is performed at 0° to 150° for 1 to 50 hours.

C. Reacting formic acid ester compounds with phosphite triestersaccording to the formula: ##STR30## wherein R₁, R₂, R₃ and R₁₀ have themeaning given above, except that R₁ must not be phenyl or a substitutedphenyl.

D. Reacting formic acid ester compounds with phosphite diester saltsaccording to the formula: ##STR31## wherein R₁, R₃ and R₁₀ have themeaning given above and M⁺ is a cation, preferably a metal such as Li⁺,Na⁺ or K⁺, and the reaction is preferably performed at 0° to 100° for 1to 50 hours in a solvent such as for example, toluene, ether ortetrahydrofurane.

The phosphite diester salts are prepared by treating the phosphitediester with a suitable proton abstracting compound, such as a metalalkoxide, suitably free from alcohol, such as litium-, sodium- orpotassium methoxide, ethoxide or t-butoxide, or with a hydride such assodium- or potassium hydride, or with a base such as butyllithium.

The starting materials used in the above methods of preparation A-D areknown compounds, or may be prepared by known methods commonly used forthe synthesis of formate esters and phosphite triesters. Examples ofmethods used for the synthesis of haloformate esters may be found in, orreferred to in M. Matzner et al Chem. Rev. 64 (1964) 645. Examples ofmethods used for the synthesis of phosphite triesters may be found inHouben-Weyl, Methoden der Organischen Chemie, Auflage 4, Band XII, Teil2, Organische Phosphorverbindungen, p. 5-78.

E. Esterification of the phosphoric acid groups ofhydroxycarbonylphosphonic acid monoester according to the formula:##STR32## R₁ and R₃ have the meaning given above. The reaction isperformed through the intermediary of activating agents known per se forthe phosphorylation of alcohols and phenols. Examples of such methodsare described for example by L. A. Slotin in Synthesis 1977, 737 and byH. Seliger and H. Kossel in Progress in the Chemistry of Organic NaturalProducts 32 (1975) 297.

Synthesis of monoesters of the carboxylic group ofhydroxycarbonylphosphonic acid are described below in methods T-X.

F. Esterification of hydroxycarbonylphosphonic acid diesters accordingto the formula: ##STR33## R₁, R₂ and R₃ have the meaning given above.

The reaction is performed through the intermediary of activating agentsknown per se for the phosphorylation of alcohols and phenols. Examplesof such methods are described for example by L. A. Slotin in Synthesis1977, 737, and by H. Seliger and K. Kossel in Progress in the Chemistryof Organic Natural Products 32 (1975) 297.

Synthesis of hydroxycarbonylphosphonic acid diesters are described belowin methods K-O.

G. Reacting oxycarbonylphosphonic acid dihalide esters according to theformula: ##STR34## Hal is Cl, Br or I and R₁ and R₃ have the meaninggiven above.

The reaction is performed by methods known per se for thephosphorylation of alcohols and phenols by phosphoric and phosphonicacid halides. Examples of such methods are described for example by L.A. Slotin in Synthesis 1977, 737 and by H. Seliger and H. Kossel inProgress in the Chemistry of Organic Natural Products 32 (1975) 297.

The oxycarbonylphosphonic acid dihalide esters are prepared fromoxycarbonylphosphonic acid monocarboxylic esters by methods known per sefor the synthesis of dihalides of phosphoric acids and phosphonic acids.References for these methods are found for example in the twopublications above and in Houben-Weyl, Methoden der Organischen Chemie,Auflage 4, Band XII/1, p. 386-406 and Band XII/2 p. 211-225 and p.274-292.

Oxycarbonylphosphonic acid monocarboxylic esters are prepared by methodsdescribed below in T-X.

H. Reacting oxycarbonylphosphonic acid monohalide diesters according tothe formula: ##STR35## Hal is Cl, Br or I and R₁, R₂ and R₃ have themeaning given above.

The reaction is performed by methods known per se for thephosphorylation of alcohols and phenols. Examples of such methods aredescribed for example by L. A. Slotin in Synthesis 1977, 737 and by H.Seliger and H. Kossel in Progress in the Chemistry of Organic NaturalProducts 32 (1975) 297.

Oxycarbonylphosphonic acid monohalide diesters are prepared fromoxycarbonylphosphonic acid diesters by methods known per se for thesynthesis of monohalides of phosphonic and phosphoric acids. Referencesfor those methods are found for example in the two publications aboveand in Houben-Weyl, Methoden der Organischen Chemie, Auflage 4, BandXII/1 p. 386-406 and XII/2 p. 211-225 and p. 274-292.

Oxycarbonylphosponic acid diesters are prepared by methods describedbelow in K-O.

J. Reacting a carbonylphosphonic acid diester according to the formula##STR36## R₁, R₂ and R₃ have the meaning given above and R₉ is asuitable activating moiety, known per se as a good leaving group insubstitution reactions on activated carboxylic acid groups. PreferablyR₉ is a group such as for example p-nitrophenoxy or imidazolyl.

The activated carbonylphosphonic acid diester used as a startingmaterial may for example be prepared by methods analogous to thesedescribed above in A-D.

Diesters of hydroxycarbonylphosphonic acid are prepared by knownmethods, such as

K. Reacting a hydroxycarbonylphosphonic acid triester with an iodide ora bromide anion, according to the formula: ##STR37## wherein X is Br orI and R₁, R₃ and R₁₁ have the meaning given above.

Preferably the reaction is carried out with sodium iodide in a solventsuch as for example tetrahydrofuran or acetone. Preferably the reactionis carried out at a temperature from 20° to 100° from 2 hours to 7 days.

The hydroxycarbonylphosphonic acid triesters may be prepared by methodsanalogous to these described above in A-H.

I. Hydrolysing the hydroxycarbonylphosphonic acid triester with a baseaccording to the formula: ##STR38## R₁, and R₃ have the meaning givenabove. R₁₂ is a hydrolyzable phosphate ester group. For example it mayhave the meaning given R₁ and R₂ and it may for example be a moregenerally substituted aryl group.

Preferably the reaction is carried out with a base such as for examplesodium hydrogencarbonate, sodiumcarbonate or sodium hydroxide in waterat a temperature from 20° to 100° from 2 hours to 7 days. Thehydroxycarbamylphosphonic acid triesters may be prepared by methodsanalogous to those described above.

M. Aqueous hydrolysis of a hydroxycarbonylphosphonic acid triester,containing one silyl esterified phosphonate group according to theformula: ##STR39## where R₂ and R₃ have the meaning given above and R₆is an inert organic residue, preferably an organic group such as forexample CH₃. Another example of silylester groups are for examplebutyldiphenylsilyl compounds, which have been described by R. A. Joneset al Bichemistry 17 (1978) 1268 as phosphate ester derivatives.

Optionally the formed phosphonic acid group may be neutralized.Preferably it may be neutralized with a base such as for example MHCO₃,M₂ CO₃ or MOH or with a weak cation exchanger (M⁺), where M⁺ is NH₄ ⁺ ora metal such as Li⁺, Na⁺, or K⁺.

The silyl esterified phosphonate group may be obtained by treating thehydroxycarbonylphosphonic acid triester with a halosilane according tothe formula: ##STR40## X is Cl, Br or I and R₂, R₃ R₆ and R₁₁ have themeaning given above.

Preferably the reagents used for silylation are for examplebromotrimethylsilane at -20° to 50° for 1/2 to 20 hours, oralternatively for example chlorotrimethylsilane at 20° to refluxtemperature for several days.

The hydroxycarbonylphosphonic acid triesters are prepared by methodsanalogous to those described above in A-J.

Alternatively the silyl esterified phosphonate group may be prepared byreacting a phosphite triester containing two silyl ester groups, with aformate ester, according to the formula: ##STR41## R₂, R₃, R₆ and R₁₀have the meaning given above.

Preferably the phosphite is an ester such as for example abis-(trimethylsilylated)phosphite triester. These compounds can beprepared by methods known per se. For example the synthesis of propyl-and cyclohexyl-bis(trimethylsilyl)phosphites are described in T. R.Herrin et al, J Med Chem 20 (1977) 660.

N. Reacting oxycarbonylphosphonic acid monocarboxylic esters accordingto the formula: ##STR42## R₁ and R₃ have the meaning given above. Thereaction is performed through the intermediary of activating agentsknown per se for the phosphorylation of alcohols and phenols. Examplesof such methods are described for example by L. A. Slotin in Synthesis1977, 737 and by H. Seliger and H. Kossel in Progress in the Chemistryof Organic Natural Products 32 (1975) 297. Optionally the phosphonicacid group may be neutralized.

Synthesis of oxycarbonylphosphonic acid monocarboxylic acids aredescribed below in methods T-X.

O. Reacting hydroxycarbonylphosphonic acid mono-P ester with anesterifying halide, using a tetraalkylammonium salt as a catalyst,according to the formula: ##STR43## Hal is Cl, Br or I, R₂ and R₃ havethe meaning given above and R₈ is an alkyl residue such as for examplen-butyl, n-pentyl, n-hexyl, n-heptyl and n-octyl. Preferably n-heptyl isused and preferably the reaction is performed as an extractivealkylation as described by for example A. Brandstrom in Preparative IonPair Extraction (Apotekersooieteton, Hassle, Sweden 1976).

Also as described the phosphonate group may be transformed to a salt##STR44## where M⁺ is for example NH₄ ⁺ or a metal such as Li⁺, Na⁺ orK⁺.

The synthesis of hydroxycarbonylphosphonic acid mono-P esters aredescribed below in methods P-S.

Monoesters of the phosphonic group of hydroxycarbonylphosphonic acid areprepared by known methods such as,

P. Hydrolyzing a hydroxycarbonylphosphonic acid triester according tothe formula: ##STR45## wherein M is a cation such as NH₄ ⁺ or Li⁺, Na⁺or K⁺ and wherein R₁₂ has the meaning given above. R₁₃ has the meaninggiven R₁₂ and R₁₂ and R₁₃ may be the same or different. R₂ is definedabove except that it must not be phenyl or substituted phenyl.

Preferably the reaction is carried out in water at 20° to 100° for 1 to10 hours.

The hydroxycarbonylphosphonic acid triesters are prepared by methodsanalogous to those described above in A-J.

Q. By the stepwise deesterification of a phosphonic acid trisubstitutedsilyl ester group, and the carboxylic acid ester group, ofhydroxycarbonylphosphonic acid triesters, according to the formula:##STR46## R₆ and R₁₃ have the meaning given above, and the silyl estergroup is preferably a group such as exemplified above in method M. R₂ isas defined above except that it must not be phenyl or substitutedphenyl.

The trimethylsilyl ester group is preferably hydrolyzed with water andthe free acid group is preferably converted to a salt by a weak cationexchanger (M⁺) or with an aqueous base such as MHCO₃, M₂ CO₃ or MOH.

The carboxylic acid ester group is preferably hydrolyzed in water andneutralized with a weak cation exchanger (M⁺) or with for example anaqueous base such as MHCO₃, M₂ CO₃ or MOH.

M⁺ is NH₄ ⁺ or a metal such as Li, Na or K.

Compounds containing the silylesterified phosphonate group may beprepared by known methods as described in method M above.

R. By the stepwise deesterification of the silyl- and the benzyl estergroup of alkyl, silyl benzyloxycarbonylphosphonate according to theformula: ##STR47##

M⁺ is NH₄ ⁺ or a metal such as for example Li⁺, Na⁺ or K⁺, and R₂ and R₆have the meaning given above except that R₂ must not be benzyl, phenylor substituted phenyl. The silyl ester group is preferably a group suchas described above in method M.

The benzyl ester group is preferably hydrogenated with a catalyst suchas for example palladiumcarbon.The free acid groups are converted totheir metal salts by the treatment with a weak cation exchanger (M⁺) orwith a base such as for example MHCO₃, M₂ CO₃ or MOH.

The silylated compound may be prepared by known methods, analogous tothose described above in M.

S. By the deesterification of the bis-silylester groups (on thephosphonic and on the carboxylic acid groups) ofhydroxycarbonylphosphonic acid triesters according to the formula:##STR48## R₂ has the meaning given above. R₆ and R₇ are inert organicresidues, the same or different, preferably they are the same and agroup such as for example CH₃. The silyl ester groups may also be forexample butyldiphenylsilyl groups as described above in method M.M⁺ isNH₄ ⁺ or a metal such as Li⁺, Na⁺ or K⁺.

The silyl ester groups are preferably hydrolyzed with for example waterand neutralized with for example a weak cation exchanger (M⁺) or anaqueous base such as MHCO₃, M₂ CO₃ or MOH.

The bis-silylated triester of hydroxycarbonylphosphonic acid may beprepared by methods known per se, according to the formula ##STR49## Halis Cl, Br or I and R₂, R₆ and R₇ have the meaning given above.

Preferably the phosphite is an ester such as for example abis(trimethylsilylated)phosphite triester. These compounds can beprepared as described above in M.

The haloformate silylesters may be prepared according to the formula:

    COCl.sub.2 +HOSi(R.sub.7).sub.3 →Cl--CO--Si(R.sub.7).sub.3 +HCl

R₇ has the meaning given above.

The reaction is carried out under anhydrous conditions, and preferably abase such as for example N,N-dimethylaniline is used for capturing thereleased hydrogenchloride. The reaction is preferably carried out in aninert solvent such as for example toluene or ether, at for example -10°to 25° for 1 to 25 hours.

Monoesters of the carboxylic group of hydroxycarbonylphosphonic acid areprepared by known methods, such as T. Aqueous hydrolysis of ahydroxycarbonylphosphonic acid triester, containing two silyl esterifiedphosphonate groups, according to the formula: ##STR50## R₃ and R₆ havethe meaning given above. Preferably R₆ is for example CH₃. The silylester derivatives may also be for example butyldiphenylsilyl groups asdescribed above in method M.

Optionally the formed phosphonic acid groups can be neutralized.Preferably they may be neutralized with a weak cation exchanger (M⁺) orwith a base such as MHCO₃, M₂ CO₃ or MOH. M⁺ is NH₄ ⁺ or a metal such asLi⁺, Na⁺ or K⁺.

The phosphonate bis-silyl esters may be obtained according to theformula: ##STR51## R₃, R₆ and R₁₁ have the meaning given above. R₁₄ hasthe meaning given R₁₁ and R₁₁ and R₁₄ may be the same or different.Preferably the organic residues of the silyl group are as describedabove. Hal is Cl, Br or I and preferably the reaction is performed at-20° to reflux temperatures for 1 hour to several days.

The hydroxycarbonylphosphonic acid triesters are prepared by methodsanalogous to those described in A-J.

Alternatively the bis silylphosphonate esters may be prepared byreacting a trissilylphosphite with a halogenformate ester according tothe formula: ##STR52## R₃, R₆ and R₁₀ have the meaning given above andpreferentially the organic residues of silyl groups are as describedabove. Preferably the reaction is performed at 20°-150° for 1 to 25hours.

The tris-silyl phosphosphites are prepared by known methods, asdescribed for example by Herrin et al in J. Med. Chem. 20 (1977) 660,for the preparation of tris(trimethylsilyl)phosphite.

U. Reacting triesters of hydroxycarbonylphosphonic acid withhydrogenhalide acids according to the formula: ##STR53## R₃, R₁₁ and R₁₄have the meaning given above. X is Cl, Br or I.

Preferably HI may be used and the reaction may preferably be performedin a dry solvent such as methylene chloride or acetic acid at atemperature from 0° to 30°. Examples of the reaction may be found in thepatents U.S. Pat. No. 3,943,201 and OT-OLS 2435 407.

Optionally the phosphonic acid groups may be neutralized. Preferably aweak cation exchanger (M⁺) or a base such as MHCO₃, M₂ CO₃ or MOH isused. M⁺ is for example NH₄ ⁺ or a metal such as Li⁺, Na⁺ or K⁺.

V. Hydrogenating dibenzyl, alkyl-oxycarbonylphonates according to theformula: ##STR54## R₃ has the meaning given above, except that it shouldnot be benzyl, phenyl or substituted phenyl.

Preferably the reaction may be performed with a catalyst such aspalladiumcarbon. Optionally the phosphonic acid groups may beneutralized. Preferably they may be neutralized with a weak cationexchanger (M⁺) or with a base such as MHCO₃, M₂ CO₃ or MOH. M⁺ is forexample NH₄ ⁺ or a metal such as Li⁺, Na⁺ or K⁺.

W. Reacting hydroxycarbonylphosphonic acid with an esterifying halide,using a tetraalkylammonium salt as a catalyst, according to the formula:##STR55## Hal is Cl, Br or I. R₃ has the meaning given above and R₈ analkyl residue, such as for example n-butyl, n-pentyl, n-hexyl, n-heptyland n-octyl. Preferably n-heptyl is used and preferably the reaction isperformed as an extractive alkylation, as described by for example ABrandstrom, Preparative Ion Pair Extraction (Apotekarsocieteten, Hassle,Sweden 1976).

Also as described, the phosphonate groups may be transformed to a disalt##STR56## where M⁺ is for example NH₄ + or a metal such as Li⁺, Na⁺ orK⁺.

X. Reacting oxycarbonylphosphonic acid diesters according to the formula##STR57## R₂ and R₃ have the meaning described above.

The preparations may be performed by procedures analogous to thosedescribed above in T-V.

Optionally the oxycarbonylphosphonic acid monocarboxylic ester thusobtained may be neutralized with a weak cation exchanger or with a basesuch as MHCO₃, M₂ CO₃ or MOH. M⁺ is for example NH₄ ⁺ or a metal such asLi⁺, Na⁺ or K⁺.

The oxycarbonylphosphonic acid diesters may be prepared by methodsdescribed above in K-N.

Preparations of triesters of hydroxycarbonylphosphonic acid.

EXAMPLE 1 Diethyl 4-methoxyphenoxycarbonylphosphonate

18.6 g (0.12 mole) of triethylphosphite was heated at 125°-130° C. in aflask with a reflux condensor. 18.6 g (0.10 mole) of 4-methoxyphenylchloroformate (prepared according to M. J. Zabik and R. D. Schuetz, J.Org. Chem. 32 (1967) 300) was added dropwise. The reaction flask washeated additionally at about 120° C. for 1,5 hours and left at roomtemperature overnight. The product was distilled to give 25.8 g (89%) ofdiethyl 4-methoxyphenoxycarbonylphosphonate. Bp₀.03 =174°-8° C., n_(D)²¹ =1,4940.

Analysis for C₁₂ H₁₇ O₆ P. Found (calculated): C 49.79 (50.00), H 6.01(5.95), P 10.54 (10.75).

NMR (CDCl₃) δ: 1.42 (t, CH₃), 3.78 (S, OCH₃), 4.13-4.63 (CH₂), 6.77-7.33(aromatic).

IR (neat) cm⁻¹ : 1740 (CO), 1275, 1255, 1190, 1030.

EXAMPLE 2

By mixing the phosphite triester and the chloroformate ester at atemperature from 20° to 130° C. and by heating at 80° to 130° C. for 1to 10 hours, the following compounds were prepared analogously toexample 1.

(a) Diethyl 4-chlorophenoxycarbonylphosphonate

From 20 g (0.12 mole) of triethylphosphite and 19.1 g (0.10 mole) of4-chlorophenyl chloroformate (prepared according to M. J. Zabik and R.D. Scheutz J. Org. Chem. 32 (1967) 300). (125° C., 2 hours). Yield 26.3g (90%). Bp₀.01 153°-6° C., n_(D) ²¹ 1.4980.

Analysis for C₁₁ H₁₄ ClO₅ P. Found (calculated): C 44.85 (45.14), H 4.83(4.82), P 10.54 (10.59).

NMR (CDCl₃) δ: 1.45 (t, CH₃), 4.17-4.63 (CH₂), 7.03-7.48 (aromatic).

(b) Dimethyl p-tolyloxycarbonylphosphonate

From 10.3 g (85 mmole) of trimethylphosphite and 10.3 g (60 mmole) ofp-tolyl chloroformate (prepared according to M. J. Zabik and R. D.Schuetz, J. Org. Chem. 32 (1967) 300). (100° C., 2 hours). Yield 93%.Bp₀.2 131° C., n_(D) ²⁰ 1.4972.

Analysis for C₁₀ H₁₃ O₅ P. Found (calculated): C 49.37 (49.18), H 5.53(5.36), P 11.71 (12.69).

NMR (CDCl₃) δ: 2.40 (CH₃), 3.92 and 4.12 (CH₃ O), 6.97-7.37 (aromaticprotons).

A second distillation gave a yield of about 80%. New analysis: C 49.13(49.18), H 5.41 (5.36), P 12.71 (12.69).

(c) Dimethyl 3,4-dichlorophenoxycarbonylphosphonate

From 10.3 g (85 mmole) of trimethylphosphite and 13.5 g (60 mmole) of3,4-dichlorophenyl chloroformate (100° C., 2 hours). Yield 11.4 g (64%).Bp₀.04 164° C., n_(D) ²⁰ 1.5271.

Solidifies to colourless crystals m.p. 58°-9° C.

Analysis for C₉ H₉ Cl₂ O₅ P. Found (calculated). C 36.06 (36.14), H 3.31(3.03), Cl 23.58 (23.71), P 10.50 (10.36).

NMR (CDCl₃) δ: 3.93 and 4.07 (CH₃ O), 7.0-7.6 (aromatic protons).

IR (KBr) cm⁻¹ : 1740 (CO), 1265, 1200, 1165, 1055, 1020.

(d) Dimethyl 2-adamantoxycarbonylphosphonate

From 1.5 g (12 mmole) of trimethylphosphite and 2.0 g (9.3 mmole) of2-adamantyl chloroformate: (100°-110° C., 2 hrs). Yield 1.0 g (37%).Bp₀.3 160° C.

NMR (CDCl₃) δ: 1.5-2.2 (adamant), 3.87 and 4.03 (CH₃ O), 5.2 (CO₂ CH).

(e) Dimethyl phenoxycarbonylphosphonate

From 10.0 ml (85 mmole) of trimethylphosphite and 10.0 g (64 mmole) ofphenylchloroformate. (100° C., 2 hours). Yield 11.0 g (75%). Bp₀.5125°-7° C. n_(D) ²⁵ 1,4907.

NMR (CDCl₃) δ: 3.90 and 4.09 (CH₃), 7.10-7.60 (C₆ H₅).

(f) Dimethyl 4-(ethoxycarbonyl)phenoxycarbonylphosphonate

From 16.1 g (0.13 mole) of trimethylphosphite and 22.8 g (0.10 mole) of4-ethoxycarbonylphenyl chloroformate. (100° C., 3 hours). Yield 26.7 g(88%). Bp₀.05 205°-7° C.

Analysis for C₁₂ H₁₅ O₇ P. Found (calculated): C 47.70 (47.69), H 5.07(5.00), P 10.15 (10.25).

NMR (CDCl₃) δ: 1.40 (t, J 7 Hz, CH₃ --C), 4.02 (d, J 11 Hz, CH₃ O), 4.36(q, J 7 Hz, CH₂), 7.27 and 8.10 (d, J 9 Hz).

IR (neat) cm⁻¹ : 1740 (CO).

(g) Diethyl 4-(ethoxycarbonyl)phenoxycarbonylphosphonate

From 21.6 g (0.13 mole) of triethylphosphite and 22.8 g (0.10 mole) of4-ethoxycarbonylphenyl chloroformate. (120° C., 2 hours). Yield 26.1 g(88%). Bp₀.01 190°-2° C. n_(D) ²⁵ 1.4890.

Analysis for C₁₄ H₁₉ O₇ P. Found (calculated): C 50.77 (50.91), H 6.20(5.80), P 9.53 (9.38).

NMR (CDCl₃) δ: 1.15-1.38 (CH₃), 4.15-4.55 (CH₂), 7.28 and 8.12 (d, J 9Hz).

(h) Diphenyl ethoxycarbonylphosphonate

[According to A. Takamizawa and Y. Sato, Chem. Pharm. Bull. 12 (1964)398]. Yield 97%, Bp₀.03 153°-5° C., n_(D) ²⁵ 1.5314.

(i) Dimethyl benzyloxycarbonylphosphonate

From 50 ml (0.4 mole) of trimethylphosphite and 56.9 g (0.3 mole) ofbenzyl chloroformate (Sigma 90-95%) (100° C., 2 hours). Yield 73 g(90%). Bp₀.02 135°-6° C. n_(D) ²⁵ 1,4997.

NMR (CDCl₃) δ: 3.75 and 3.97 (CH₃), 5.28 (s, CH₂), 7.37 (s, C₆ H₅).

(k) Diethyl methoxycarbonylphosphonate

[According to T. Reetz et al. J. Amer. Chem. Soc. 77 (1955) 3813]. Yield87%, Bp₁ 87°-91° C., n_(D) ²² 1.4235.

NMR (CDCl₃) δ: 1.20 (t, J 6 Hz, CH₃ --C), 3.83 (s, CO₂ CH₃), 4.03-4.52(J 6 Hz, CH₂).

IR (neat) cm⁻¹ : 1725 (CO).

(1) Dimethyl n-butoxycarbonylphosphonate

From 10.0 ml (85 mmole) of trimethylphosphite and 8.7 g (64 mmole) ofn-butyl chloroformate. (100° C., 1.5 hours).

Yield 10.9 g (81%). Bp₁.0 97°-100° C. n_(D) ²⁵ 1,4269.

NMR (CDCl₃) δ: 0.80-1.08 (CH₃ --C), 1.15-1.80 (CH₂ --CH₂), 3.80 and 4.02(CH₃ O), 4.20-4.41 (OCH₂).

(m) Dimethyl i-propoxycarbonylphosphonate

From 10.0 ml (85 mmole) of trimethylphosphite and 7.8 g (64 mmole) ofi-propyl chloroformate. (100° C., 2 hours).

Yield 8.0 g (64%). Bp₂ 90°-2° C. n_(D) ²⁵ 1,4202.

NMR (CDCl₃) δ: 1.39 (d, J 6 Hz, C--CH₃), 3.80 and 3.98 (CH₃ O), 5.0-5.4(CH).

(n) di-n-butyl methoxycarbonylphosphonate

From 26.6 g (0.10 mole) of tri-n-butylphosphite and 18.9 g (0.20 mole)of methyl chloroformate (80° C., 6 hours).

Yield 22.4 g (89%). Bp₀.2 85°-105° C., n_(D) ²⁵ 1.4310.

NMR (CDCl₃) δ: 0.80-1.03 (CH₃), 1.18-1.98 (CH₂ --CH₂), 3.85 (s, CO₂CH₃), 4.23 (q, J 6 Hz, OCH₂).

(o) Triethyloxycarbonylphosphonate

[According to P. Nylen, Ber. 57 (1924) 1023]. Yield 85-90%. Bp₁₆136°-141° C., n_(D) ²⁴ 1.4225.

(p) Dimethyl cyclohexoxycarbonylphosphonate

From 24.8 g (0.20 mole) of trimethylphosphite and 32.1 g (0.20 mole) ofcyclohexylchloroformate, (Y. Iwakura and A. Nabeya, J. Org. Chem. 25(1960) 1118; M. E. Fourneau et al. Chem. Abstr. 16 (1922) 240; J. H.Saunders et al. J. Am. Chem. Soc. 73 (1951) 3797). (100° C., 2 hours).Yield 30 g (54%). Bp₁.4-1.8 148°-151° C. n_(D) ²¹ 1.4543.

Analysis for C₉ H₁₇ O₅ P. Found (calculated): C 45.97 (45.76), H 7.27(7.26), P 13.37 (13.12).

NMR (CDCl₃) δ: 1.3-2.0 (CH₂), 3.83 and 4.03 (CH₃), 5.1 (CH).

(q) Dimethyl cyclopentylmethylenoxycarbonylphosphonate

From 12.4 g (0.10 mole) of trimethylphosphite and 16.26 g (0.10 mole) ofcyclopentylmethylchloroformate. (100° C., 2 hrs).

Yield 14.4 g (61%). Bp₁.5-2.0 150°-4° C., n_(D) ²¹ 1.4549.

(r) Dimethyl ethoxycarbonylphosphonate

From 10,0 ml (85 mmole) of trimethylphosphite and 10.0 ml (105 mmole) ofethyl chloroformate (100° C., 1,5 hours). Yield 12,5 g (80%). Bp₁₅ 122°C.

NMR (CDCl₃) δ: 1,33 (t, J 7 Hz, CH₃ --C), 3,88 (d, J 11 Hz, CH₃ O), 4,36(quintet, J 7 Hz, CH₂ --C).

Analysis for C₉ H₁₇ O₅ P. Found (calculated): C 45.80 (45.76), H 7.30(7.26), P 12.97 (13.11).

NMR (CDCl₃) δ: 1.1-2.6 (cyclopentyl), 3.87 and 4.05 (CH₃), 4.12 (CH₂, d,J 7 Hz).

EXAMPLE 3 Ethyl, p-methoxyphenyl phenoxycarbonylphosphonate

24.4 g (0.10 mole) of diethyl p-methoxyphenylphosphite and 31.2 g (0.20mole) of phenyl chloroformate were mixed at room temperature and heated130° C. for about 2 hours. The excess of phenyl chloroformate wasevaporated at 130° C. with a vacuum pump, to give the product as aresidue.

n_(D) ²⁵ 1.5378. NMR (CDCl₃) δ: 1.42 (t, J 7 Hz, CH₃ --C), 3.80 (s, CH₃O), 4.50 (quintet, J 7 Hz, CH₂), 6.76-7.70 (9H).

IR (neat) cm⁻¹ : 1740, 1590, 1500, 1180, 980 and 920.

EXAMPLE 4

Analogously as described in example 3, the following compounds wereprepared by heating at 20°-130° C. for 2-15 hours.

(a) Ethyl, p-chlorophenyl phenoxycarbonylphosphonate

From 24.9 g (0.10 mole) of diethyl p-chlorophenylphosphite and 31.3 g(0.20 mole) of phenyl chloroformate. (110° C., about 15 hours).

NMR (CDCl₃) δ: 1.47 (t, J 7 Hz, CH₃ --C), 4.50 (quintet, J 7 Hz, CH₂),7.0-7.7 (aromatic).

(b) Ethyl, 3,4-dichlorophenyl phenoxycarbonylphosphonate

From 14.2 g (0.05 mole) of diethyl 3,4-dichlorophenylphosphite and 15.7g (0.10 mole) of phenyl chloroformate (110° C., about 15 hours).

NMR (CDCl₃) δ: 1.46 (t, J 7 Hz, CH₃), 4.50 (quintet, J 7 Hz, CH₂),7.0-7.6 (aromatic).

(c) Ethyl, 2,6-dimethylphenyl methoxycarbonylphosphonate

From 20.0 g (83 mmole) of diethyl 2,6-dimethylphenylphosphite and 10.0ml (127 mmole) of methyl chloroformate. (100° C., 4 hours). Yield 22.2 g(99%). By g.l.c. (3% OV 17 column, 120°-280° C.) only one peak was seen.

NMR (CDCl₃) δ: 1.35 (t, J 7 Hz, CH₃ --C), 2.37 (s, CH₃ --Ar), 3.92 (s,CO₂ CH₃), 4.40 (quintet, J 7 Hz, CH₂), 7.03 (s, C₆ H₃).

An analytical sample was distilled in vacuo. Bp₀.04 125°-8° C. n_(D) ²⁵1.4914.

(d) Ethyl, 5-indanyl methoxycarbonylphosphonate

From 20.0 g (78 mmole) of diethyl 5-indanylphosphite and 10.0 ml (127mmole) of methyl chloroformate (100° C., 4 hours).

Yield 22 g (99%). By g.l.c. (3% OV17 column, 120°-280° C.) the puritywas estimated to be about 85%.

NMR (CDCl₃) δ: 1.40 (t, J 7 Hz, CH₃ --C), 1.85-2.35 (multiplet, CH₂),2.80-3.05 (CH₂ --C--CH₂), 3.82 (s, CO₂ CH₃), 4.42 (quintet, J 7 Hz, CH₂O), 6.9-7.3 (C₆ H₃).

(e) Methyl 1-adamantyl methoxycarbonylphosphonate

From 24.4 g (0.1 mole) of dimethyl 1-adamantylphosphite and 18.9 g (0.2mole) of methyl chloroformate (90° C., 2 hours).

NMR (CDCl₃) δ: 1.63 and 2.16 (broad singlets. C₁₀ H₁₅), 3.83 (s, CO₂CH₃), 3.88 (d, J 12 Hz, OCH₃). IR (neat) cm⁻¹ : 1730, 1290, 1230, 1060,1020, 990.

An analytical sample was distilled in vauco. B.p.₀.01, 125°-7°. n_(D) ²⁵1.4922.

(f) Methyl p-acetylphenyl methoxycarbonylphosphonate

From 11.4 g (50 mmole) of dimethyl p-acetylphenylphosphite and 9.5 g(100 mmole) of methyl chloroformate (100° C., 1 hour and 120° C., 2hours). n_(D) ²⁵ 1.5178.

NMR (CDCl₃) δ: 2.60 (s, CH₃ --CO), 3.92 (s, CO₂ CH₃), 4.08 (d, J 11 Hz,OCH₃), 7.39 and 8.03 (doublets, J 9 Hz, C₆ H₄).

IR (neat) cm⁻¹ : 1730, 1690, 1610, 1510, 1370, 1300, 1270, 1250, 1220,1050, 950.

(g) Ethyl p-acetylphenyl methoxycarbonylphosphonate

From 12,8 g (50 mmole) of diethyl p-acetylphenylphosphite and 9,5 g (100mmole) of methylchloroformate (120°, 6 hours) n_(D) ²⁵ 1,5152. NMR(CDCl₃) δ: 1,41 (t, J 7 Hz, .tbd.CH₃ --C), 2,60 (s, CH₃ --CO), 3,89 (s,CH₃ --O), 4,45 (quintet, J 7 Hz, CH₂), 7.40 and 8,03 (doublets, J 9 Hz,C₆ H₄).

IR (neat) cm⁻¹ : 1730, 1690, 1600, 1510, 1370, 1290, 1270, 1240, 1210,1030, 950.

EXAMPLE 5 Dibenzyl ethoxycarbonylphosphonate

Ethanol (4.6 g) was added to a fine suspension of sodium metal (2.25 g)in dry ether (200 ml) under an atmosphere of nitrogen. The mixture washeated for 8 hours, after which dibenzylphosphite (25.7 g) in dry ether(50 ml) was added. After standing over-night the dibenzylphosphitesodium salt was added over a period of 2 hours to a cold solution ofethyl chloroformate (10.8 g) in ether, under an atmosphere of nitrogen.The reaction was heated at reflux for 1 hour, cooled, washed with water,a NaCl solution and dried over Na₂ SO₄. The ether was evaporated. Afterevaporating and discarding components volatile at 0.01 mm and 150° C.the residue was collected (13 g).

Analysis: NMR (CDCl₃): 1.10-1.25 (CH₃), 4.03-4.50 (CO₂ CH₂), 5.00-5.32(CH₂), 7.39 (C₆ H₅). IR (neat): 1720 cm⁻¹ (CO).

Examples of methods used for the synthesis of haloformate esters.

EXAMPLE 6 3,4-Dichlorophenyl chloroformate

40.75 g (0.25 mole) of 3,4-dichlorophenol in 135 ml of dry toluene wascautiously added to 240 ml (0.46 moles) of a 20% solution of phosgene intoluene. The reaction flask was equipped with a stirrer, a dry icecondensor and a dropping funnel, and the reaction temperature was20°-25° C. 31.5 g (0.26 moles) of N,N-dimethylaniline was added over aperiod of 45 min and the flask was left without stirring for 2 hours.The precipitate was filtered off and washed with 2×25 ml of toluene. Thecombined toluene solutions were cooled on ice and quickly washed with 50ml of water, 100 ml of 0.1N HCl and 100 ml of water. The solution wasdried over magnesium sulfate and evaporated on a rotary evaporator. Theresidue was distilled in vacuo over a Vigreux column, to give 46.4 g(82%) of 3,4-dichlorophenylchlorformate, bp₂₀ 134° C. The productbecomes slightly blue and crystallizes in long needles, m.p. 51°-53° C.

EXAMPLE 7 2-Adamantanyl chloroformate

15.2 g (0.10 mole) of 2-adamantanol and 12.1 g (0.10 mole) ofN,N-dimethylaniline were dissolved in 200 ml of dry ether and added to105 ml (0.20 mole) of phosgene in toluene (20%) over a period of 1 hour.The reaction flask was kept at 0° C. and was equipped with a stirrer anda dry ice condensor. The product was stirred at room temperature foranother hour, after which the solution was cooled on ice and 10 ml ofice cold water was added carefully. The water and the toluene phaseswere quickly separated and the toluene was quickly washed with 50 ml of0.5N HCl, 50 ml of 0.5N NaOH and 50 ml of H₂ O. The toluene solution wasdried over magnesium sulfate and evaporated in vacuo. The residue wasdissolved in dry n-hexane and filtered. The hexane was evaporated andthe residue was distilled in vacuo to give 2-adamantanyl chloroformatebp₁₅ 135° C., n_(D) ¹⁹ 1.521, IR (CO) 1770 cm⁻¹.

EXAMPLE 8 Cyclopentylmethylmethylene chloroformate

A mixture of 24.2 g (0.20 mole) N,N-dimethylaniline and 20.3 g (0.20mole) of cyclopentylmethanol was slowly added to a 20% solution ofphosgene in toluene (104 ml, 0.20 mole) cooled to -5° to +5° C. Afterthe addition the reaction mixture was allowed to attain room temperatureand was kept at room temperature for 30 min. The precipitate wasfiltered off and the solvent was evaporated. Distillation in vacuo gave26.3 g (81%) of cyclopentylmethyl chloroformate. Bp₁₇₋₂₀ 82°-84° C.,n_(D) ²¹ 1.4541. Analysis for C₇ H₁₁ ClO₂. Found (calculated): Cl 21.37(21.80). IR (neat) cm⁻¹ : 1790 (CO).

EXAMPLE 9 4-Ethoxycarbonylphenyl chloroformate

From 49.9 g (0.3 mole) of 4-hydroxybenzoic acid ethylester, 40 ml (0.3mole) of N,N-dimethylaniline and 0.4 mole of a 20% solution of phosgenein toluene, 54.4 g (79%) of 4-ethoxycarbonylphenyl chloroformate wasobtained. Bp₁₀ 146°-146.5° C., n_(D) ²⁵ 1.5140. IR (neat) cm⁻¹ : 1720and 1790 (CO).

Examples of methods used for the synthesis of triesters of phosphorousacid.

EXAMPLE 10 Diethyl p-methoxyphenylphosphite

The synthesis was carried out by the method described by W. G. Bentrude,E. R. Hansen, W. A. Khan, T. B. Min and P. E. Rogers, J. Amer. Chem.Soc. 95 2292 (1973) for the preparation of diethyl phenylphosphite.

A solution of 50.0 g (0.364 mole) of phosphorous trichloride in 500 mlof anhydrous ether was stirred (mechanically) under an atmosphere ofargon. The temperature was maintained at -20°--15° C. during theaddition of 37.1 g triethylamine, followed by the slow addition ofp-methoxyphenol, 45.19 g (0.364 mole) in 200 ml of dry ether over aperiod of 2.5 hours. When the addition was complete another portion oftriethylamine 73.8 g (0.728 mole), was added, followed by the slowaddition of absolute ethanol, 33.5 g (0.728 mole), in 50 ml of dry ether(1.5 hours). The mixture was stirred at room temperature over night. Themixture was warmed and allowed to reflux for 1 hour. The triethylaminehydrochloride was filtered off and was washed with dry ether. Thesolvent was removed under reduced pressure. Distillation of the residualoil yielded 48.6 g of diethyl p-methoxyphenylphosphite, bp₁₁₀ (1.2mm)-102 (0.6 mm). Another 4.20 g was obtained at 0.2 mm bp 92°-96° C.n_(D) ²⁰ 1.4993.

Analysis for C₁₁ H₁₇ O₄ P. Found (calculated). C 54.14 (54.10), H 7.07(7.02), P 12.74 (12.68).

NMR (CDCl₃) δ: 1.26 (t, J 7 Hz, CH₃), 3.70 (s, CH₃ O), 4.00 (quintet, J7 Hz, CH₂), 6.7-7.1 (m, C₆ H₄).

IR (neat) cm⁻¹ : 2980, 1510, 1220, 1030, 920.

EXAMPLE 11.

Analogously as described in Example 10, the following phosphites wereprepared.

(a) Diethyl p-chlorophenylphosphite

Yield 43%. Bp₁.5 102°-104° C., n_(D) ²⁵ 1.5047.

NMR (CDCl₃) δ: 1.17 (t, J 7 Hz, CH₃), 4.00 (quintet, J 7 Hz, CH₂),6.9-7.3 (C₆ H₄).

IR (neat) cm⁻¹ : 2980, 1590, 1490, 1390, 1230, 1030, 920.

(b) Diethyl 3,4-dichlorophenylphosphite

Yield 18%. Bp₀.02 110° C., n_(D) ²⁵ 1.5188.

Analysis for C₁₀ H₁₃ Cl₂ O₃ P. Found (calculated): C 42.47 (42.43), H4.55 (4.63), Cl 25.11 (25.05), P 10.33 (10.94).

NMR (CDCl₃) δ: 1.30 (t, J 7 Hz, CH₃), 4.03 (quintet; J 7 Hz, CH₂),6.9-7.5 (C₆ H₃).

IR (neat) cm⁻¹ : 2980, 1590, 1570, 1470, 1390, 1260, 1220, 1120, 1030,900.

(c) Dimethyl p-acetylphenylphosphite

Yield 20%. Bp₀.03 128°-130° C., n_(D) ²⁵ 1.5308.

Analysis for C₁₀ H₁₃ O₄ P. Found (Calculated): C 52.36 (52.64), H 5.74(5.74), P 13.33 (13.57).

NMR (CDCl₃) δ: 2.58 (s, CH₃ CO), 3.68 (d, J 11 Hz, CH₃ O), 7.14 and 7.97(d, J 9 Hz).

(d) Dimethyl 1-adamantylphosphite

Yield 50% (crude product).

NMR (CDCl₃) δ: 1.63 and 2.0-2.2 (adamantyl), 3.50 (d, J 11 Hz, CH₃ O).

(e) Diethyl 2,6-dimethylphenylphosphite

Yield 29%. Bp₀.01 84°-5° C.

NMR (CDCl₃) δ: 1.30 (t, J 7 Hz, CH₃ --C), 2.33 (s, CH₃ --Ar), 4.03(quintet, J 7 Hz, CH₂ O), 7.00 (s, C₆ H₃).

(f) Diethyl 5-indanylphosphite

Yield 29%. Bp₀.01 140° C.

NMR (CDCl₃) δ: 1.30 (t, J 7 Hz, CH₃), 1.95-2.30 (CH₂), 2.97-3.03 (CH₂--C--CH₂), 4.03 (quintet, J 7 Hz, CH₂ O), 6.7-7.3 (C₆ H₃).

Preparation of diesters of hydroxycarbonylphosphonic acid.

(g) Diethyl p-acetylphenylphosphite

Yield 21%. Bp₀.02 142°-158° C. n_(D) ²⁵ 1.5194. NMR (CDCl₃) δ: 1.33 (t,J 7 Hz, CH₃ --C), 2.60 (S, CH₃ --CO), 4.08 (quintet, J 7 Hz, CH₂ --C),7.90 and 8.00 (doublets, J 9 Hz).

EXAMPLE 12 Sodium methyl benzyloxycarbonylphosphonate ##STR58##

3.66 g of dimethyl benzyloxycarbonylphosphonate and 2.25 g of sodiumiodide were stirred in 25 ml of dry tetrahydrofuran for 3 days. Theprecipitate was filtered, washed with ether and dried in a desiccator.Colourless, hygroscopic crystals of the title compound were obtained(3.15 g, 82%). By t.l.c. (polyethyleneimine, 1M LiCl, molybdate spray)the compound was estimated to contain <0.4% of trisodiumoxycarbonylphosphonate.

Analysis for C₉ H₁₀ NaO₅ P×1/4H₂ O. Found (calculated): H₂ O 1.7%(1.75); Na 8.8% (8.96); Molecular weight by titration 257 (256.6).

NMR (D₂ O) δ: 3.57 and 2.76 (CH₃), 5.28 singlet (CH₂), 7.48 singlet (C₆H₅).

EXAMPLE 13

Analogously with example 12, the following compounds were prepared bytreating the respective triester with sodium iodide. The purificationprocedure was somewhat modified.

(a) Sodium n-butyl methoxycarbonylphosphonate

From di-n-butyl methoxycarbonylphosphonate (3.78 g). The collectedreaction product (1.65 g) was dissolved in water (10 ml) and added toacetone (100 ml). After filtration the solvent was evaporated. Theresidue was triturated with aceton, centrifuged and dried in adesiccator, to yield colourless crystals (0.46 g, 14%). Thin layerchromatography: Silica gel, eluted with ethanol and visualized withiodine vaper R_(f) 0.46.

By t.l.c. (polyethyleneimine, 1M LiCl, molybdate spray) the compound wasestimated to contain <0.4% of trisodium oxycarbonylphosphonate.

Analysis for C₆ H₁₂ NaO₅ P. Found (calculated): Na 10.8% (10.54);Molecular weight (by titration) 218.8 (218.1).

(b) Sodium ethyl ethoxycarbonylphosphonate

From hydroxycarbonylphosphonic acid triethyl ester (3.15 g). Thereaction precipitate (0.35 g) was centrifuged, washed with ether,dissolved in water (10 ml) and the water solution was washed with ether.The solution was evaporated in vacuo (3 mm) at room temperature. Ethanolwas added to the residue and evaporated. The residue was treated withether and dried in a desiccator. Colourless crystals (0.29 g, 9%) wereobtained. By t.l.c. (polyethyleneimine, 1M LiCl, molybdate spray) thecompound was estimated to contain <0.4% of trisodiumoxycarbonylphosphonate.

Analysis for C₅ H₁₀ NaO₅ P. Found (calculated): Na 11.7% (11.26);Molecular weight (by titration) 204.0 (204.1).

EXAMPLE 14 Sodium phenyl ethoxycarbonylphosphonate ##STR59##

Diphenyl ethoxycarbonylphosphonate (3.06 g) and sodium hydrogencarbonate(0.84 g) were stirred in water (10 ml) at room temperature for about 24hours. The solvent was evaporated and the residue extracted withethanol. The ethanol was evaporated and the residue was washed withether. The residue was recrystallized twice from isopropanol. Colourlesscrystals (0.67 g, 27%) were obtained.

Thin layer chromatography on silica gel, eluted with ethanol anddeveloped with iodine vapor: R_(f) 0.66. By t.l.c. the compound wasestimated to contain <0.4% of trisodium oxycarbonylphosphonate.

Analysis for C₉ H₁₀ NaO₅ P. Found (calculated): C 42.99 (42.87), H 3.73(4.00), Na 9.12 (9.12), P 12.12 (12.28). Molecular weight by titration253.8 (252.1).

Reactions involving a trimethylsilyl group:

EXAMPLE 15 Sodium 2,6-dimethylphenyl methoxycarbonylphosphonate

11.1 g (41 mmole) of ethyl 2,6-dimethylphenyl methoxycarbonylphosphonateand 12.7 g (83 mmole) of bromo trimethylsilane were stirred under anitrogen atmosphere for about 3 days.

Excess of bromotrimethylsilane was evaporated in vacuo (0.5 mm) and 4.62g (14 mmole) of the residue (total 12.7 g) was added to 60 ml of waterand 27.8 g (60 meq.) of Amberlite IRC 50 (Na⁺). The mixture was stirredfor about 2 days, and filtered. The solution was evaporated in vacuo,redissolved in 50 ml of water and washed with ether (3×25 ml). Thesolution was evaporated in vacuo, the residue was dissolved in 50 ml ofethanol and 200 ml of ether was added. The precipitate wasrecrystallized twice from i-propanol to give 1.77 g (45%) of the titlecompound. By t.l.c. (polyethyleneimine, 1M LiCl, molydate spray) thecompound was shown to contain <0.4% of trisodium oxycarbonylphosphonate.

Analysis for C₁₀ H₁₂ O₅ PNa. Found (calculated): Na 8.64 (9.0).

NMR (D₂ O) δ: 2.30 (s, CH₃ --Ar), 3.91 (s, CO₂ CH₃), 7.12 (s, C₆ H₃). IR(KBr) cm⁻¹ : 1730, 1700, 1490, 1260, 1180, 1100, 920.

EXAMPLE 16

Analogously as described in example 15, the following compounds wereprepared.

(a) Sodium 5-indanyl methoxycarbonylphosphonate

From ethyl 5-indanyl methoxycarbonylphosphonate. Yield 16%. By t.l.c.(polyethyleneimine, 1M LiCl, molybdate spray) the compound was shown tocontain <0.4% of trisodium oxycarbonylphosphonate.

Analysis for C₁₁ H₁₂ O₅ PNa. Found (calculated): Na 8.3 (8.3).Equivalent weight by titration: 279.1 (278.2).

NMR (D₂ O) δ: 1.8-2.3 and 2.7-3.1 (CH₂ --CH₂ --CH₂), 3.83 (s, CO₂ CH₃),6.9-7.4 (C₆ H₃).

IR (KBr) cm⁻¹ : 1720, 1500, 1280, 1260, 1210, 1140, 1100, 960.

(b) Sodium 1-adamantyl methoxycarbonylphosphonate

From 11.5 g (0.04 mole) of methyl 1-adamantylmethoxycarbonylphosphonate.

The crude product (11.5 g) was dissolved in 100 ml of warm water, andfiltered. The solution was evaporated and the residue was dissolved in50 ml of water. 400 ml of ethanol was added, the solution was filteredand evaporated in vacuo to give 4.85 g (40%) of the title compound afterthe residue had been washed with ethanol and dried.

By t.l.c. (polyethyleneimine, 1M LiCl, molybdate spray) the compound wasshown to contain <1% of trisodium oxycarbonylphosphonate).

NMR (D₂ O) δ: 1.50 and 1.85 (broad singlets, C₁₀ H₁₅), 3.62 (s, CO₂CH₃).

Preparation of monoesters of hydroxycarbonylphosphonic acid (of thephosphonic acid group).

EXAMPLE 17 Methyl disodium oxycarbonylphosphonate

The synthesis was carried out analogously by the method described inpatent DT-OLS 2435407 (W. Abitz, D. F. Morf and H. A. Brauns).

Dimethyl benzyloxycarbonylphosphonate (6.2 g) in water (50 ml) wasstirred and 50% aqueous NaOH (4.0 g) was added dropwise. The mixture washeated at reflux for 1 hour, after which the solution was evaporated invacuo. The product was redissolved in water (10 ml) and methanol (80 ml)was added slowly. The precipitate was filtered and dried (2.60 g). Lateranother 0.55 g of the title compound precipitated slowly from thesolution in the form of its disodium salt.

By t.l.c. (PEI, 1M LiCl, molybdate spray) the compound was shown tocontain <0.5% trisodium oxycarbonylphosphonate.

Analysis for C₂ H₃ Na₂ O₅ P. Found (calculated): Na 24.9% (24.99);Equivalent weight 92.6 (92.0). (By titration).

NMR (D₂ O) δ: 3.45 and 3.63 (CH₃).

IR (KBr) cm⁻¹ : 1590 (CO), 1085 (P--O⁻), 1055 (POCH₃).

(b) Ethyl disodium oxycarbonylphosphonate

5.25 g (25 mmole) of triethyl oxycarbonylphosphonate and 50 ml of 1Naqueous NaOH were heated at reflux for 2 hours. The solvent wasevaporated, the residue was redissolved in 10 ml of H₂ O and 15 ml ofethanol was added. The precipitate was filtered and discarded. Another40 ml of ethanol was added to the solution. The precipitate was filteredand collected. 1.5 g (30%). NMR (CDCl₃) δ: 1.25 (t, J 7 Hz, CH₃), 3.95(quintet, J 7 Hz, CH₂).

EXAMPLE 18 1-Adamantyl disodiumoxycarbonylphosphonate

11.5 g (0.04 mole) of methyl 1-adamantyl methoxycarbonylphosphonate and12.5 g (0.08 mole) of bromotrimethylsilane were stirred under a nitrogenatmosphere, at room temperature overnight. Excess ofbromotrimethylsilane was evaporated in vacuo (about 0.3 mm) at 50° C.The residue was stirred with 80 ml (0.08 mol) of 1N aqueous NaOH at roomtemperature for two hours, after which the solvent was evaporated invacuo.

The residue (12.06 g) was dissolved in 150 ml of water, filtered and 350ml of ethanol was added to the solution. The precipitate was filteredoff (5.47 g), redissolved in 100 ml of water and 60 ml of ethanol wasadded. The new precipitate (A) was filtered off (2.83), and another 350ml of ethanol was added to the solution to give another 2.15 g ofprecipitate (B). Precipitate B was redissolved in 50 ml of water; 20 mlof ethanol was added and the precipitate was discarded. Another 400 mlof ethanol was added, the precipitate was collected by centrifugation,to give, after drying, 1.49 g of the title compound. By performingtwice, this purification scheme on precipitate A, another 1.92 g of thetitle compound could be collected.

Both fractions could by t.l.c. (polyethyleneimine, 1M LiCl, molybdatespray) be estimated to contain <1% of trisodium oxycarbonylphosphonate.R_(f) (the same system) 0.57 single spot.

NMR (D₂ O) δ: 1.50 and 1.93 (broad singlets). IR (KBr) cm⁻¹ : 1580 (CO),1380, 1240, 1200, 1090, 1060, 990.

Preparation of monoesters of the carboxylic group ofhydroxycarbonylphosphonic acid.

EXAMPLE 19 Disodium ethoxycarbonylphosphonate

1.20 g (5.7 mmole) of triethyl oxycarbonylphosphonate and 2.65 g (17.2mmole) of bromotrimethylsilane were stirred at room temperature in adried flask under an atmosphere of argon. After about 3 hours, volatilecomponents were evaporated in vacuo (1 mm) and the residue was added to16 g of Amberlite IRC 50 (Na⁺, 1.3 meq/g) in 25 ml of water. After 1.5hours the ion exchanger was added to a column and eluted with another 25ml of water. The combined water phases (50 ml) were washed with diethylether, filtered and evaporated in vacuo (3 mm Hg) at room temperature.The residue was washed with ethanol, filtered and dried in a desiccator,to yield 1.88 (88%) of colourless crystals of the title product.

T.l.c. (polyethyleneimine, 1.4M LiCl, molybdate spray): R_(f) 0.58.

By t.l.c. (1M LiCl) the compound was estimated to contain <0.4% oftrisodium oxycarbonylphosphonate.

Analysis for C₃ H₅ Na₂ O₅ P×5H₂ O. Found (calculated): H₂ O 11.8 (12.0),Na 20.7 (20.4). Molecular weight by titration: 232 (225).

NMR (D₂ O) δ: 1.23 (t, J 7 Hz, CH₃), 4.18 (quartet, J 7 Hz, CH₂).

EXAMPLE 20

Analogously as described in example 19, the following reactions andanalyses were performed.

(a) Disodium n-butoxycarbonylphoshonate

From dimethyl n-butoxycarbonylphosphonate. Yield 92%. T.l.c. R_(f) 0.52.By t.l.c. (1M LiCl) compound was estimated to contain <0.5% of trisodiumoxycarbonylphosphonate.

Analysis for C₅ H₉ Na₂ O₅ P×1.5H₂ O. Found (calculated): H₂ O 10.6(10.7), Na 18.7 (18.2). Molecular weight 262 (253).

NMR (D₂ O) δ: 0.9 (CH₃), 1.2-1.8 (CH₂ --CH₂), 4.1 (OCH₂).

(b) Disodium i-propoxycarbonylphosphonate

From dimethyl i-propoxycarbonylphosphonate. Yield 90%. T.l.c. R_(f)0.53. By t.l.c. (1M LiCl) the compound was estimated to contain <0.4% oftrisodium oxycarbonylphosphonate.

Analysis for C₄ H₇ Na₂ O₅ P×1.5H₂ O. Found (calculated): H₂ O 11.6(11.3), Na 19.1 (19.2). Molecular weight: 234 (239).

NMR (D₂ O) δ: 1.20 (d, J 6 Hz, CH₃), 4.93 (m, CH).

(c) Disodium benzyloxycarbonylphosphonate

From dimethyl benzoxycarbonylphosphonate. Yield 88%. T.l.c. R_(f) 0.37.By t.l.c. (1M LiCl) the compound was estimated to contain <0.4% oftrisodium oxycarbonylphosphonate.

Analysis for C₈ H₇ Na₂ O₅ P×1.5H₂ O. Found (calculated): H₂ O 9.2 (9.4),Na 16.4 (16.0).

NMR (D₂ O) δ: 5.14 (s, CH₂), 7.37 (s, C₆ H₅).

(d) Disodium cyclohexoxycarbonylphosphonate

From dimethyl cyclohexoxycarbonylphosphonate. The crude product waspurified by precipitation with ethanol from a water solution. Yield 87%.T.l.c. R_(f) 0.54. Single spot. By t.l.c. the compound was estimated tocontain <0.5% of trisodium oxycarbonylphosphonate.

NMR (D₂ O) δ: 1.2-2.0 (m, C₆ H₁₁). IR(KBr) cm⁻¹ : 1670 (CO), 1120 and990 (PO₄ ³⁻).

(e) Disodium cyclopentylmethylenoxycarbonylphosphonate

From dimethyl cyclopentylmethylenoxycarbonylphosphonate. The crudeproduct was purified by precipitation with ethanol from a watersolution. Yield 67%. T.l.c. R_(f) 0.55. Single spot. By t.l.c. thecompound was estimated to contain <0.5% of trisodiumoxycarbonylphosphonate.

NMR (D₂ O) δ: 1.1-1.19 [m, (CH₂)₄ ], 2.0-2.3 (m, CH), 3.98 (d, J 7 Hz,CO₂ CH₂).

IR (KBr) cm⁻¹ : 1680 (CO), 1130 and 1000 (PO₄ ³⁻).

(f) Disodium 2-adamantoxycarbonylphosphonate

From dimethyl 2-adamantoxycarbonylphosphonate. Yield 80%. T.l.c. R_(f)0.56. Single spot. By t.l.c. the compound was estimated to contain <1%of trisodium oxycarbonylphosphonate.

NMR (D₂ O) δ: 1.43-2.20 (C₁₀ H₁₄), 4.93 (CO₂ CH). IR (KBr) cm⁻¹ : 1680(CO), 1120 and 980 (PO₄ ³⁻).

Pharmaceutical compositions

The following examples illustrate the preparation of pharmaceuticalcompositions of the invention. The active substance in case it can formsalts, is preferably used in the form of its sodium salt.

EXAMPLE 21 Aerosol for inhalation

    ______________________________________                                        Active substance      1.00     g                                              Miglyol ®         0.20     g                                              Frigen ® 11/12/113/114                                                                          ad 100.0 g                                              ______________________________________                                    

EXAMPLE 22 Tablets

    ______________________________________                                        Each tablet contains:                                                         ______________________________________                                        Active substance       20.0   mg                                              Maize starch           25.0   mg                                              Lactose                190.0  mg                                              Gelatin                1.5    mg                                              Talc                   12.0   mg                                              Magnesium stearate     1.5    mg                                                                     250.0  mg                                              ______________________________________                                    

EXAMPLE 23 Suppositories

    ______________________________________                                        Each suppository contains:                                                    Active substance          20.0     mg                                         Ascorbyl palmitate        1.0      mg                                         Suppository base (Imhausen H or Witespol ® H)                                                       ad 2000.0                                                                              mg                                         ______________________________________                                    

EXAMPLE 24 Syrup

    ______________________________________                                        Active substance (as its sodium salt)                                                                 0.200    g                                            Liquid glucose          30.0     g                                            Sucrose                 50.0     g                                            Ascorbic acid           0.1      g                                            Sodium pyrosulfite      0.01     g                                            Disodium edetate        0.01     g                                            Orange essence          0.025    g                                            Certified colour        0.015    g                                            Purified water          ad 100.0 g                                            ______________________________________                                    

EXAMPLE 25 Injection solution

    ______________________________________                                        Active substance (as its sodium salt)                                                                 0.500    mg                                           Sodium pyrosulfite      0.500    mg                                           Disodium edetate        0.100    mg                                           Sodium chloride         8.500    mg                                           Sterile water for injection                                                                           ad 1.00  ml                                           ______________________________________                                    

EXAMPLE 26 Inhalation solution

    ______________________________________                                        Active substance       5.00     g                                             Sodium pyrosulfite     0.10     g                                             Disodium edetate       0.10     g                                             Sodium chloride        0.85     g                                             Purified water         ad 100.0 ml                                            ______________________________________                                    

EXAMPLE 27 Sublingual tablets

    ______________________________________                                        Active substance      5.0    mg                                               Lactose               85.0   mg                                               Talc                  5.0    mg                                               Agar                  5.0    mg                                                                     100.0  mg                                               ______________________________________                                    

EXAMPLE 28 Drops

    ______________________________________                                        Active substance       2.00     g                                             Ascorbic acid          1.00     g                                             Sodium pyrosulfite     0.10     g                                             Disodium edetate       0.10     g                                             Liquid glucose         50.00    g                                             Absolute alcohol       10.00    g                                             Purified water         ad 100.0 ml                                            ______________________________________                                    

EXAMPLE 29 Syrup

    ______________________________________                                        Active substance       0.200    g                                             Liquid glucose         30.0     g                                             Sucrose                50.0     g                                             Ascorbic acid          0.1      g                                             Disodium edetate       0.01     g                                             Orange essence with solubilizer                                                                      0.25     g                                             Hydrochloric acid to pH 6.0-8.0                                               Purified water         ad 100.0 g                                             ______________________________________                                    

EXAMPLE 30 Solution for injection

    ______________________________________                                        Active substance       0.500    mg                                            Disodium edetate       0.100    mg                                            Sodium chloride for isotonia q.s.                                             Hydrochloric acid to pH 6.5-8.0                                               Starile water for injection                                                                          ad 1.00  ml                                            ______________________________________                                    

EXAMPLE 31 Solution for inhalation

    ______________________________________                                        Active substance (as its sodium salt)                                                                 5.00     g                                            Disodium edetate        0.10     g                                            Sodium chloride         0.85     g                                            Hydrochloric acid to pH 6.0-8.0                                               Purified water          ad 100.0 ml                                           ______________________________________                                    

EXAMPLE 32 Drops

    ______________________________________                                        Active substance (as its sodium salt)                                                                  2.00     g                                           Citric acid              1.00     g                                           Disodium edetate         0.10     g                                           Liquid glucose           50.00    g                                           Ethanol 95%              10.00    g                                           Sodium hydroxide and hydrochloric acid                                        to pH 6.2-6.8                                                                 Purified water           ad 100.0 ml                                          ______________________________________                                    

EXAMPLE 33 Solution for topical use

    ______________________________________                                        Active substance (as its sodium salt)                                                                 2.00     g                                            Isopropanol             38.0     g                                            Glycerol                13.6     g                                            Hydrochloric acid to pH 5.0-8.5                                               Purified water          ad 100.0 g                                            ______________________________________                                    

Preparations containing 0.2, 0.5 and 1.0 g of active substance.

EXAMPLE 34 Jelly

    ______________________________________                                        Active substance (as its sodium salt)                                                                  4.0      g                                           Methocel ®           4.0      g                                           Methyl paraoxybenzoate   0.12     g                                           Propyl paraoxybenzoate   0.05     g                                           Sodium hydroxide and hydrochloric acid                                        to pH 6.6-8.5                                                                 Distilled water          ad 100.0 ml                                          ______________________________________                                    

EXAMPLE 35 Ointment I

    ______________________________________                                        Active substance (as its sodium salt)                                                                 2.5      g                                            Cetyltrimethylammonium bromide                                                                        0.6      g                                            Stearyl alcohol         2.25     g                                            Cetanol                 6.75     g                                            Liquid paraffine        17.0     g                                            Glycerol                12.0     g                                            Hydrochloric acid to pH 6.0-8.5                                               Distilled water         ad 100.0 g                                            ______________________________________                                    

Preparations containing 0.2, 0.5, 1.0 and 2.0 g of active substance havealso been prepared.

EXAMPLE 36 Ointment II

    ______________________________________                                        Active substance (as its sodium salt)                                                                 2.5      g                                            Polyethylene glycol 1500                                                                              50.0     g                                            Polyethylene glycol 4000                                                                              15.0     g                                            Propylene glycol        ad 100.0 g                                            ______________________________________                                    

EXAMPLE 37 Ointment III

    ______________________________________                                        Active substance (as its sodium salt)                                                                 3.0      g                                            Sorbitan monoleate      5.0      g                                            Petrolatum              ad 100.0 g                                            ______________________________________                                    

EXAMPLE 38 Gastric juice-resistant tablets

Tablets according to Example 22 are coated with an enteric coatingsolution with the following composition:

    ______________________________________                                        Cellulose acetate phtalate                                                                         120.0      g                                             Propylene glycol     30.0       g                                             Sorbitan monoleate   10.0       g                                             Ethanol 95%          450.0      ml                                            Acetone              q.s. ad 1000.0                                                                           ml                                            ______________________________________                                    

The coating is carried out by a pouring procedure in a conventionalcoating pan or by spraying the tablets in a pan spray tablet coater.

EXAMPLE 39 Eye drops

    ______________________________________                                        Active substance (as sodium salt)                                                                    0.1      g                                             Disodium edetate       0.10     g                                             Sodium chloride for isotonia q.s.                                             Hydrochloric acid to pH 6.5-8.0                                               Methocel ® 65 HG 4000                                                                            0.65                                                   Sterile water          ad 100   ml                                            ______________________________________                                    

EXAMPLE 40 Eye drops

    ______________________________________                                        Active substance (as sodium salt)                                                                    1.0      g                                             Disodium edetate       0.10     g                                             Sodium chloride for isotononia q.s.                                           Hydrochloric acid to pH 6.5-8.0                                               Methocel ® 65 HG 4000                                                                            0.65                                                   Sterile water          ad 100   ml                                            ______________________________________                                    

EXAMPLE 41 Eye Ointment

    ______________________________________                                        Active substance (as its sodium salt)                                                                 5        g                                            Paraffin oil            19       g                                            Petrolatum              76       g                                            ______________________________________                                    

EXAMPLE 42 Cream

    ______________________________________                                        Active substance          3.0      g                                          Arlaton ®             4.0      g                                          Cetanol                   2.0      g                                          Stearic acid              2.0      g                                          Paraffin oil              2.0      g                                          Propylene glycol          2.0      g                                          Glycerol                  1.5      g                                          Methyl-p-hydroxybensoate  0.06     g                                          Propyl-p-hydroxybensoate  0.03     g                                          Sodium hydroxide          0.002    g                                          Hydrochloric acid 2 M to pH 8.0 (water phase)                                 Distilled water           ad 100   g                                          ______________________________________                                    

EXAMPLE 43 Jelly

    ______________________________________                                        Active substance       3.0      g                                             Methocel ®         2.45     g                                             Glycerol               10.0     g                                             Tween ®            0.10     g                                             Methyl-p-hydroxybensoate                                                                             0.06     g                                             Propyl-p-hydroxybensoate                                                                             0.03     g                                             Sodiumhydroxid         0.002    g                                             Hydrochloric acid 2 M to pH 8.0                                               Distilled water        ad 100   g                                             ______________________________________                                    

Biological tests I. Inhibition of virus multiplication in cell cultureA. Inhibition of herpes simplex type 1 plaque

The plaque reduction assay for herpes simplex type 1 was performed onGMK (Green Monkey Kidney) cells as described by Ejereito et al. J. Gen.Virol. 2 (1968) 357. Monolayers on 5 cm petri dishes were used and aftervirus adsorption the test compound was added in the medium. The resultsare shown below.

Inhibition of herpes simplex type 1 plaque on GMK monolayers

    __________________________________________________________________________    Test compound                                                                  ##STR60##                            compoundtestConc.                                                                   Inhibition                        R.sub.1                                                                              R.sub.2    R.sub.3       Code (μm)                                                                             (%)                                __________________________________________________________________________    Na     Na         2-adamantyl   VIS 131                                                                            500   76; 0; ˜50                   Na     Na         2-adamantyl   VIS 131                                                                            100   40                                  ##STR61##                                                                            ##STR62## C.sub.2 H.sub.5                                                                             VIS 035                                                                            500   74; 0; >90                         C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                           ##STR63##    VIS 236                                                                            500   82                                 CH.sub.3                                                                             CH.sub.3                                                                                  ##STR64##    VIS 243                                                                            500   56                                 C.sub.2 H.sub.5                                                                       ##STR65##                                                                                ##STR66##    VIS 057                                                                            500   90                                 Na                                                                                    ##STR67## CH.sub.3      VIS 441                                                                            500   98                                 Na                                                                                    ##STR68## CH.sub.3           100   >90                                __________________________________________________________________________

B. Inhibition of influenza (WSN Wilson Smith Neurotropic type A.) plaque

The method for plaque assay of influenza has been described by Bentleyet. al, Archiv fur die Gesamte Virusforschung 33 (1971) 234.

Monolayers of MDCK (Madin Darby Canine Kidney) cells on 5 cm plasticpetri dishes were inoculated with 100 plaque-forming units of influenzavirus (WSN). After virus adsorption, 5 ml of agarose overlay containingdifferent concentrations of the test compound were added and the plateswere incubated at 34° C. for 4 days. The plaques formed at this timewere counted. The results are shown below.

Inhibition of influenza (WSN Wilson Smith Neurotropic type A) plaque onGMK monolayers.

    __________________________________________________________________________    Test compound                                                                  ##STR69##                       compoundtestConc. of                                                                Inhibition                             R.sub.1                                                                          R.sub.2   R.sub.3       Code (μm)                                                                             (%)                                     __________________________________________________________________________    C.sub.2 H.sub.5                                                                  C.sub.2 H.sub.5                                                                          ##STR70##    VIS 236                                                                            500   69                                      CH.sub.3                                                                         CH.sub.3                                                                                 ##STR71##    VIS 416                                                                            500   68                                      CH.sub.3                                                                         CH.sub.3                                                                                 ##STR72##    VIS 243                                                                            500   73                                      C.sub.2 H.sub.5                                                                  C.sub.2 H.sub.5                                                                          ##STR73##    VIS 241                                                                            500   90; 66                                  Na                                                                                ##STR74##                                                                              CH.sub.3      VIS 441                                                                            500   75                                      __________________________________________________________________________

II. Inhibition of cutaneous herpes on guinea pigs

The effect on cutaneous herpes simplex type 1 infections have beenmeasured in a guinea pig model described by Hubler et al. J. Invest.Dermatol. 69 (1974) 92. The compounds have been tested as topicalapplications of 30 μl of 2% solution of the compound in 45% (v/v)isopropanol 10% (v/v) glycerol and 45% water (v/v) or 10% glycerol, 0.1%tween, water twice daily for 4 days starting 4 or 24 hours afterinfection. The appearance of an infected treated area and a similarinfected untreated (only isopropanol-glycerol-water) area was scoreddaily on a scale from 0 to 3. The total effect is judged from the scoreat day 5.

    ______________________________________                                        Test compound                                                                  ##STR75##                 Score at day 5                                     R.sub.1 R.sub.2  R.sub.3                                                                             Code     treated                                                                             untreated                               ______________________________________                                        Na      CH.sub.3 Na    VIS 018  0     3 (1)                                   1-ada-  Na       Na    VIS 078  1     3 (2)                                   mantyl                                                                        ______________________________________                                         (1) Start of treatment 4 h after infection                                    (2) Start of treatment 24 h after infection                              

III. Stability test

The acid stability was investigated by dissolving 5 mg of each compoundin 1 ml of 0.1N HCl in a test tube. For use as references 0.2 ml of eachsolution was withdrawn, immediately treated with 0.2 ml of a 10% aqueoussolution of NaHCO₃ and frozen. The remaining 0.8 ml of each solution wasincubated at 37° C. for 2 hours. After incubation, 0.8 ml of a 10%aqueous solution of NaHCO₃ was added to each solution and the solutionswere frozen. The incubated compounds and the reference compounds werelyophilized to dryness and redissolved in distilled H₂ O, 0.2 ml and 1.0ml respectively, for each reference solution and incubated solution. Thesolutions were applied to silica gel (Merck PF₂₅₄, 20×20 cm) andpolyethylene imine (Macherey-Nagel PEI, 20×20 cm) thin layer plates. Atotal of 20 μl of the reference solutions (100 μg compound) and 25 μl ofthe incubated solutions (100 μg compound) were applied. To each platewas also added, as references, solutions of phosphorous acid (H₂ HPO₃)(5 and 20 μg) and of trisodiumphosphonoformate (5 and 20 μg).(Decomposition of phosphonoformic acid at low pH produces phosphorousacid).

The silica gel plates were prepared in duplicate and eluted with asolution composed of methanol--10% aq ammonia-trichloroacetic acid-water(50-15-5-3, v/v) and the polyethylene imine plates were eluted with a 1Maq lithium chloride solution. After elution the plates were dried. Oneof the duplicated silica gel plates was sprayed with 4% aq (NH₄)₂ MoO₄and the polyethylene imine plates were sprayed with a solution composedof 60% HClO₄ --0.1N aq HCl--4% aq (NH₄)₂ MoO₄ --H₂ O (5-10-25-60, v/v).The silica gel plates were briefly dried at 80°-90° C. and sprayed with1% SnCl₂ in 10% aq HCl. Phosphorous acid and phosphonic acid groupsappeared as blue spots on the silica gel plates (System 1) and as whitespots on the polyethylene imine plates (System II). The remainingduplicate silica gel plates were exposed to iodine vapor for detectionof di- and triesters of phosphonoformic acid.

    ______________________________________                                                       R.sub.f System I                                                                      R.sub.f System II                                      ______________________________________                                        Phosphorous acid 0.31      0.71                                               Na.sub.3 --phosphonoformate                                                                    0         0.21                                               ______________________________________                                    

The formation of phosphorous acid and phosphonoformic acid in eachincubated solution was estimated and the results are given below. Thefigures for the non-incubated reference compounds are given inparenthesis.

    __________________________________________________________________________    Test Compound                                                                  ##STR76##                   acidformatephosphorousphono-Na.sub.3 phos-Est                                imated formation of                               R.sub.1                                                                              R.sub.2                                                                              R.sub.3  Code (μg)                                                                              (μg)                                    __________________________________________________________________________    Na     Na                                                                                    ##STR77##                                                                             VIS 409                                                                            N.D. (N.D.)                                                                          N.D. (N.D.)                                Na     C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                        VIS 414                                                                            N.D. (N.D.)                                                                          N.D. (N.D.)                                Na     n-C.sub.4 H.sub.9                                                                    CH.sub.3 VIS 047                                                                            N.D. (N.D.)                                                                          N.D. (N.D.)                                Na     CH.sub.3                                                                              ##STR78##                                                                             VIS 406                                                                            N.D. (N.D.)                                                                          N.D. (N.D.)                                C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                        EHB 783                                                                            N.D. (N.D.)                                                                          N.D. (N.D.)                                C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                      CH.sub.3 VIS 224                                                                            N.D. (N.D.)                                                                          N.D. (N.D.)                                n-C.sub.4 H.sub.9                                                                    n-C.sub.4 H.sub.9                                                                    CH.sub.3 VIS 046                                                                            N.D. (N.D.)                                                                          N.D. (N.D.)                                CH.sub. 3                                                                            CH.sub.3                                                                             n-C.sub.4 H.sub.9                                                                      VIS 415                                                                            N.D. (N.D.)                                                                          N.D. (N.D.)                                CH.sub.3                                                                             CH.sub.3                                                                              ##STR79##                                                                             VIS 416                                                                            N.D. (N.D.)                                                                          N.D. (N.D.)                                CH.sub.3                                                                             CH.sub.3                                                                              ##STR80##                                                                             VIS 405                                                                            N.D. (N.D.)                                                                          N.D. (N.D.)                                 ##STR81##                                                                            ##STR82##                                                                           C.sub.2 H.sub.5                                                                        VIS 035                                                                            N.D. (N.D.)                                                                          N.D. (N.D.)                                CH.sub.3                                                                             CH.sub.3                                                                             i-C.sub.3 H.sub.7                                                                      VIS 419                                                                            N.D. (N.D.)                                                                          N.D. (N.D.)                                Na     CH.sub.3                                                                             Na       VIS 018                                                                            N.D. (N.D.)                                                                          N.D. (N.D.)                                Na     Na     Na       EHB 776                                                                            20 (N.D.)                                         __________________________________________________________________________     N.D. = Not detectable (much less than 5 μg)                           

IV. In vivo metabolization

Metabolization of compounds of the invention was tested in NMR I 19-20 gmale mice. The test compound (10 μmol) was dissolved in 0.5 ml salineand injected intraperitoneally. Two mice kept in one cage (formetabolization experiment) were used for each compound. The urineobtained from the two mice on day 1, 2 and 3 after the injections wascollected. The urine was diluted with Tris-HCl buffer (pH 7.9) to aconstant volume of 1 ml. This volume was then diluted 1:500, 1:5000 and1:50000 with the same buffer and assayed for phosphonoformic acidactivity on cell-free influenza polymerase. The assay mixture whichincludes Mn²⁺ and assay conditions are described by Bishop, Obijeski andSimpson, J. Virol. 8, 66 (1971). Phosphonoformic acid in diluted urinegave 50% inhibition at 0.5 μM in this assay and was used as a standardto estimate the amount of phosphonoformic acid activity formed in theurine from compounds of the invention.

    ______________________________________                                                        Recovered phosphonoformic                                                     acid activity in urine                                                        (μmol phosphonoformic acid)                                Test compound     Day 1    Day 2    Day 3                                     ______________________________________                                         ##STR83##        0.05     0.05     0.40                                       ##STR84##        1.25     0.13     <0.01                                     ______________________________________                                    

Acute toxicity

A preliminary acute toxicity test was carried out in mice. Groups of twomale mice of the NMR I strain weighing 20-21 g received the testcompound in doses of 62.5-500 mg/kg i.p. The compound was given as asolution in 0.9% NaCl. The number of animals dead 24 hrs after injectionwas as follows.

    ______________________________________                                                         Dose                                                                          mg/kg    No of animals dead                                  Test compound    i.p.     No of animals injected                              ______________________________________                                         ##STR85##       62.5 125 250 500                                                                           0/2 0/2 0/2 0/2                                  ##STR86##       62.5 125 250 500                                                                           0/2 0/2 0/2 0/2                                  ##STR87##       62.5 125 250 500                                                                           0/2 0/2 0/2 1/2                                 ______________________________________                                    

Discussion of test results

As seen in test I compounds of the invention are active on herpes virusand influenza virus multiplication in cells. As seen in test IIcompounds of the invention are also active on cutaneous herpes in theguinea pig. According to the stability test III, compounds of theinvention are more stable than trisodium phosphonoformate in 0.1Maqueous HCl, which is a model for stability in gastric juice, and thecompounds of the invention should therefore be more suitable for oraladministrations than phosphonoformic acid and physiologically acceptablesalts thereof. The test on in vivo metabolism IV shows that compounds ofthe invention are metabolized to phosphonoformic acid measured asphosphonoformic acid activity on influenza polymerase. It is also shownin test IV that compounds according to the invention can give such anactive metabolite in the urine of mice over a longer time period thantrisodium phosphonoformate. Thus compounds of the invention have aprolonged activity in comparison with phosphonoformic acid and itsphysiologically acceptable satls. The acute toxicity test shows thatcompounds of the invention have a low acute toxicity, i.e. high LD50values. In conclusion compounds of the invention have antiviral effectson herpes and influenza viruses and low toxicity. Furthermore compoundsof the invention can be bio-transformed to phosphonoformic acid orionized forms thereof which have strong activities against viralfunctions and virus multiplication.

We claim:
 1. A method for treatment of viral infections in animalsincluding man, comprising administering to an animal so infected acompound of the formula ##STR88## wherein R₁ is selected from the groupconsisting of hydrogen, alkyl containing 1-6 carbon atoms, cycloalkylcontaining 3-6 carbon atoms, cycloalkyl-alkyl containing 4-6 carbonatoms, 1-adamantyl, 2-adamantyl and benzyl; R₂ is hydrogen and R₃ isselected from the group containing hydrogen and benzyl, provided thatwhen R₃ is H, then R₁ is alkyl, cycloalkyl or cycloalkyl-alkyl asdefined above, or 1-adamantyl, 2-adamantyl or benzyl, or aphysiologically acceptable salt or an optical isomer thereof in anamount sufficient for treating said viral infections.
 2. A methodaccording to claim 7, wherein the virus is selected from the groupconsisting of herpes virus, influenza virus and hepatitis B virus.
 3. Amethod for the treatment of viral infections in animals including man,by inhibiting the activity of viral polymerase, comprising administeringto an animal so infected a compound of the formula ##STR89## wherein R₁is selected from the group consisting of hydrogen, alkyl containing 1-6carbon atoms, cycloalkyl containing 3-6 carbon atoms, cycloalkyl-alkylcontaining 4-6 carbon atoms, 1-adamantyl, 2-adamantyl and benzyl; R₂ ishydrogen and R₃ is selected from the group containing hydrogen andbenzyl, provided that when R₃ is H, then R₁ is alkyl, cycloalkyl orcycloalkyl-alkyl as defined above, or 1-adamantyl, 2-adamantyl orbenzyl, or a physiologically acceptable salt or an optical isomerthereof in an amount sufficient for inhibiting the activity of saidviral polymerase.
 4. A method for inhibiting the activity of viralreverse transcriptase in animals including man, comprising administeringto an animal in need of such treatment a compound of the formula##STR90## wherein R₁ is selected from the group consisting of hydrogen,alkyl containing 1-6 carbon atoms, cycloalkyl containing 3-6 carbonatoms, cycloalkyl-alkyl containing 4-6 carbon atoms, 1-adamantyl,2-adamantyl and benzyl; R₂ is hydrogen and R₃ is selected from the groupcontaining hydrogen and benzyl, provided that when R₃ is H, then R₁ isalkyl, cycloalkyl or cycloalkyl-alkyl as defined above, or 1-adamantyl,2-adamantyl or benzyl, or a physiologically acceptable salt or anoptical isomer thereof in an amount sufficient for inhibiting theactivity of said reverse transcriptase.
 5. A method for inhibiting thegrowth of virus-transformed cells in animals including man, comprisingadministering to an animal in need of such treatment a compound of theformula ##STR91## wherein R₁ is selected from the group consisting ofhydrogen, alkyl containing 1-6 carbon atoms, cycloalkyl containing 3-6carbon atoms, cycloalkyl-alkyl containing 4-6 carbon atoms,1-adamantyl-2-adamantyl and benzyl; R₂ is hydrogen and R₃ is selectedfrom the group containing hydrogen and benzyl, provided that when R₃ isH, then R₁ is alkyl, cycloalkyl or cycloalkyl-alkyl as defined above, or1-adamantyl-2-adamantyl or benzyl, or a physiologically acceptable saltor an optical isomer thereof in an amount sufficient for inhibiting saidgrowth.
 6. A method as in any of claims 1, 3, 4 or 5 wherein, in thecompound of the formula I, the radicals R₁ and R₂ are hydrogen and R₃ isbenzyl.
 7. A method as in any of claims 1, 3, 4 or 5 wherein thecompound is in the form of its sodium salt.